American Journal of Medical Genetics 42:431-448 (1992)

Molecular Nosology of Heritable Disorders of Connective Tissue P. Beighton, A. De Paepe, J.G. Hall, D.W. Hollister, F.M. Pope, R.E. Pyeritz, B. Steinmann, and P. Tsipouras Cape Town, South Africa ( P B . ) ; Ghent, Belgium (A. de P.);Vancouver, Canada (J.GJI.1; Portland, (D.W.H.); London, England (F.M.P.); Baltimore, Maryland (R.E.P.), Zurich, Switzerland (B.S.), Farmington, Connecticut (P.T.) INTRODUCTION The heterogeneity of the heritable connective tissue disorders (HCTD) has created problems with syndromic boundaries, nomenclature, and classification. These difficulties were discussed at a workshop held during the 7th International Congress of Human Genetics in Berlin in 1986, and a nosology was subsequently formulated [Beightonet al., 19881. This nosology,which is popularly known as the Berlin Nosology of Heritable Connective Tissue Disorders, represents a consensus of opinions concerning syndrome definitions and terminology, from the standpoint of the phenotype. Extensive subclassification in the Berlin phenotypic nosology was necessitated by the great heterogeneity of these disorders. In light of the continuing elucidation of biomolecular defects of collagen, it was initially anticipated that subcategorisation could be based on the underlying molecular and collagen abnormalities. This system would be in accordance with precedents established in the mucopolysaccharidoses and related disorders. Unfortunately, this approach was confounded by the fact that mutations a t the same connective tissue gene locus can produce widely disparate phenotypes; indeed, the same faulty gene can underlie conditions that are conventionally regarded as distinct syndromic entities. This dilemma was debated by an expert committee that met at the Ciba Foundation in London, and in Corfu under the auspices of the European Consortium for Heritable Connective Tissue Disorders. The problem was resolved by the construction of a second nosology, based on a systematic tabulation of abnormalities at the different collagen gene loci. Information concerning the corresponding protein changes and the syndromic phenotype was provided, together with key references. By using the phenotypic (Berlin) nosology and this new molecular ~

Received for publication February 5,1991; revision received July 23, 1991. David Hollister died during the formulation of this manuscript. The authors held him in high esteem as a friend and a colleague; this article is dedicated to his memory. Address reprint requests to Professor P. Beighton. Department of Human Genetics, Medical School, University of Cape Town, Observatory 7925, South Africa.

0 1992 Wiley-Liss, Inc.

(London)nosology in parallel, it will be possible to relate abnormalities of the collagen genes and proteins to specific phenotypes and vice versa, thus facilitating clinicopathological correlations. The London Molecular Nosology concerns collagen types 1-111 inclusively, and as very little is known about the phenotypic correlations of collagens IV-XIV, these have been omitted. Loci for genes other than collagens, together with candidate proteins, have also been listed if these are involved, or potentially involved, with the HCTDs. In view of the importance of homologies in the elucidation of gene defects, relevant mouse loci are also tabulated. The format of the nosology is flexible, and it will be possible to accommodate new information as and when it becomes available in the future. The contents of the molecular nosology are listed below, and the names of the individual contributors are indicated: COLlA1: D.W. Hollister COLlA2: P. Tsipouras COLBAl: D.W. Hollister COLSAl: F.M. Pope and A. de Paepe Other gene loci and candidate proteins R.E. Pyeritz Mouse loci relevant to HCTDs J.G. Hall

CONVENTIONS USED FOR TABULAR DATA The data summarized below are listed by individual gene loci, which are designated by the protein product. The locus symbol, size, and chromosomal location of the gene are indicated. Known molecular defects are then presented in tabular form, followed by provisional defects and linkage data (which include instances in which a disease has been excluded from linkage with the locus in question). An abbreviated format has been adopted for the tabular data, and the reader should refer to the followinginformation regarding the abbreviations used: i) Diseases: (refer to Beighton et al., [19881for clinical subtypes) 01 = osteogenesis imperfecta EDS = Ehlers-Danlos syndrome SEDc = spondyloepiphyseal dysplasia congenita Ach-Hyp = achondrogenesis I1 (or 1B)-hypochondrogenesis OP = osteoporosis OA = osteoarthritis

PMm; exon 48 G(52) to T LMd,f; exon 52 del of GAA’IT after G(108) PMm,s; intron 14 G(5)to A LMi: insertion approx. 600 bp between exons 13-19 PMm; exon 20 G(2) to T LMd; del exons 23-25 PMm; exon 25 PMm; exon 32

166200 Hetero

166200 Hetero

166200 Hetero

166210 Homo

166210 Hetero

166210 Hetero

166210 Hetero

166210 Hetero

166210 Hetero

01, Type 1

01, Type I

01, Ywe 1

01, Type I1

01, Type I1

01, Type I1

01, Type I1

01, Type I1

01, Type I1

01, Type I1

References Comments Nicholls et al., 1990 Jt. hypermobility, osteoporosis, no fractures Rediagnosed as 01 Nicholls et al., 1990 Late-onset fractures

Helical Helical Helical

PMm; exon 32 G(55) Gly(550) to Arg toA Gly(568) to Asp PMm; exon 33 PMm; exon 33 PMm; exon 35

PMm; exon 36 G(82) Gly(667) to Arg to A PMs; exon 36 PMm; exon 37 PMm; exon 39

166210 Hetero

166210 Hetero

166210 Hetero

166210 Hetero

166210 Hetero

166210 Hetero

166210 Hetero

166210 Hetero

166210 Hetero

166210 Hetero

01, Type I1

01, Type I1

01, Type I1

01, m e I1

01, Type I1

01, Type I1

01, Type I1

01, Type I1

01, Type I1

Helical Helical

Gly(718) to Cys

PMm; exon 39 Gly(748) to Cys G(109) to T PMm; exon 41 G(92) Gly(832) to Asp toA

Helical

Helical

Helical

Helical

Gly(691) to Cys

Gly(673) to Asp

Gly(631) to Ser

Helical

Helical

Gly(541) to Asp

Gly(598) to Ser

Cohn et al., 199Oc

Helical

Gly(391) to Arg

Cohn et al.. 1990a

Father mosaic

Parent mosaic; presumably G(2) to A Westerhausen et al., Presumably, G(91) 1990 to A Westerhausen et al., Presumably, G(28) 1990 to A Bateman et al., 1988; Baker et al., 1989 Cohn et al., 199Oc Parent mosaic; presumably G(101) to A Presumably G(46) Prockop, 1990 to T Starman et al., Presumably, G(19) 1989 to T Vogel et al., 1987

Wallis et al., 1990a

Helical

84 aa deleted

Intron to intron deletion Presumably G(37) toC Presumably, G(29) toA Father mosaic

Helical

Gly(256) to Val

Patterson et al., 1989 Barsh et al., 1985 Chu et al., 1985 Bateman et al., 1987 Zhuang et al., 1990

Byers et al., 1988

Helical

Insertion of 50-70 aa

Del exon 14 (18 aa)

Bonadio et al., 1990 Alternative splicing

Starman et al., Presumably G(10) 1989 to T C-telopeptide Cohn et al., 1988 Labhard et al., 1988 C-Propeptide Willing et al., 1990 F’rameshift

Helical

Helical

Domain Helical

Helical

Additional 84 missense aa

Gly(3) to Cys

LMd,s; 11bp del Del exon 9 (18 aa) ( + 3- + 13) intron 9 PMm; exon 12 Gly(94) to Cys

166200 Hetero

01, Type 1

Protein change Gly(19) to Cys

TABLE I. COLlAl: Known Mutations

Mutation Disease MIM # Zygosity 01, Type I/EDS 166200 Hetero PMm; exon 7 G(1) to T

Helical Helical

Helical

PMm; exon 47 Gly(964) to Ser PMm; exon 47 G(29) Gly(973) to Val PMm; exon 47 G(37) Gly(976) to Arg toA PMm; exon 47 G(73) Gly(988) to Cys toT PMm; exon 48 Gly(1003) to Ser PMm; exon 48 G(20) toT LMi,f; exon 49 i(T) after T(57) PMm; exon 17 G(1) toT PMm; exon 31 PMm; exon 42 G(19) Gly(844) to Ser to A PMm; exon 26 G(10) Gly(415) to Cys to T PMm; exon 48 Gly(1009) to Ser PMm; exon 17 Gly(178) to Cys PMm; exon 32 G(55) Gly(550) to Arg toA PMm; exon 41 G(91) Gly(832) to Ser

166210 Hetero

166210 Hetero

166210 Hetero 166210 Hetero

166210 Hetero

166210 Hetero

166210 Hetero

166210 Hetero

166210 Hetero Hetero

259420* Hetero

259420" Hetero

259420* Hetero

166220 Hetero 166220 Mosaic

166220 Hetero

130060 Hetero

01, Type I1

01, Type I1

01, Type I1 01, Type I1

01, Type I1

01, !type I1

01, Type I1

01, Type I1

01, Type I1

Variable 01 I/IV/III 01, m e I11

01, Type I11

01, Type I11

01, Type IV/I 01, Type IV

01, Qpe IV

EDS, Type VIIA

A

PMm.s: exon 6 G(72) to A

tn

Helical

24 aa of exon 6 deleted

Gly(526) to Cys

Cohn et al., 1990b Helical

N-teloDeDtide weil et al., 1989 _ -

Marini et al., 1989

Cetta et al., 1990 Wallis et al., 1990a

Nicholls et al., 1990

Starman et al., 1989 Pack et al., 1989

Lamande et al., 1989 Bateman et al., 1989 Wirtz et al., 1990

Cohn et al., 1990b

I

Alternative splicing

Gonadal, other mosaicism, offspring with lethal 01

Presumably G(28) tQA

Presumably G(82) to T

Frameshift

Presumably, G(10) to A

Parent mosaic; presumably G(83) to A Constantinou et al., Mother mosaic 1989 Cohn et al., 1990b Presumably G(10) to A Lamande et al., 1989 Wallis et al., 1990b + 1 or + 2 mutation, intron 47 Wallis et al., 1990b Lamande et al., 1989 Lamande et al., 1989 Cohn et al., 1986

Cohn et al., 199Oc

Helical

Helical

Helical

Truncated, missense C-propeptide C-propeptide Gly(175) to Cys Helical

Gly(1006) to Val

Helical

Helical

Helical

Helical Helical

Helical

Helical

Helical

Wallis et al., 1990b Presumably G(28) to A or C Wallis et al., 1990b

*Although 01-III is classified as a recessive condition in Mendelian Inheritance in Man [McKusick,19901, these patients clearly have a dominant disorder, as do many persons with this phenotype.

01, Type 111-IV 259420" Hetero

PMm; exon 45 G(56) Gly(928) to Ala Helical toC PMs; del exon 47 Del exon 47 (36 aa) Helical

166210 Hetero

01, Type I1

toT

PMm; exon 44 G(37) Gly(904) to Cys toT PMm; exon 45 Gly(913) to Ser

166210 Hetero

01, Type I1

Gly(883) to Asp

166210 Hetero

01, Type I1

Helical

Del aa 874-876

LMd; exon 43 del 9 bP PMm; exon 43

166210 Hetero

01, Type 11

Helical

Gly(847) to Arg

PMm; exon 43

166210 Hetero

01, Type I1

434

Beighton et al.

Stickler syndrome = hereditary progressive arthroophthalmopathy ii) MIM #: Accession number for specific disease as listed in Mendelian Inheritance in Man, 9th ed. [McKusick, 19901. iii) Zygosity: Homo = homozygous or compound, implying autosomal recessive inheritance Hetero = heterozygous, implying autosomal dominant inheritance Hemi = hemizygous, implying inheritance on the X chromosome iv) Mutation: PMm = point mutation, missense PMs = point mutation, splicing LMd = length mutation, deletion LMi = length mutation, insertion (secondary effects of LM: s = splicing; f = frameshift) Nucleotide(s) changes are denoted by the normal base followed by a number indicating the position within the designated exon or intron, and the abnormal nucleotide observed. v) Protein change: The normal amino acid and position within the designated protein domain is given, followed by the abnormal amino acid observed or inferred from the mutant RNA and/or DNA sequence, a a = amino acid. vi) Domain: N-propeptide = amino-terminal precursor-specific peptide; N-telopeptide = amino-terminal nonhelical junctional peptide linking N-propeptide to the helical domain; helical = large central triple helical domain; C-telopeptide = carboxyl-terminal nonhelical junctional peptide uniting the helical domain with the C-propeptide; C-propeptide = carboxyl-terminal precursor-specific peptide.

TYPE I COLLAGEN COLlAl Gene: alpha 1 chain of type I collagen; alpha 1(I) Locus symbol: COLlAl Size: 18 kilobases Chromosomal location: 17q21-22 [Myers and Emanuel, 19871 Linkage Data Disorders linked to COLlAl: 01, Q p e I and Q p e IV [Sykes et al., 1986; Sykes et al., 19901. Disorders not linked to COLlAl: Marfan syndrome [Ogilvie et al., 1987; Boileau et al., 1990; Schwartz et al., 19901 Mitral valve prolapse syndrome [Wordsworth et al., 19891 01 (some forms) [Aitchison et al., 19881

Linkage Data Disorders linked to COLlA2: 01, Type IV [Tsipouras et al., 1984; Sykes et al., 19901 TYPE I1 COLLAGEN COL2A1 Gene: alpha 1 chain of type I1 collagen, alpha l(I1) Locus symbol: COL2Al Size: 30 kilobases [Sangiorgi et al., 19851 Chromosomal location: 12q121-123 [Myers and Emanuel, 19871 Linkage Data Disorders linked to COL2A1: SEDc [Anderson et al., 1990al SEDc, Namaqualand type [Sher et al., 19911 Osteoarthritis [SEDc] [Palotie et al., 1989; Knowlton e t al., 19901 Stickler syndrome (some families) [Francomano et al., 1988a; Knowlton et al., 19891 Disorders not linked to COL2A1: Achondroplasia [Wordsworth et al., 1988; F'rancomano and Pyeritz, 1988bl Diaphyseal aclasis [Wordsworth et al., 19881 Hypochondroplasia [Wordsworth et al., 19881 Marfan syndrome [Ogilvie et al., 1987; Boileau et al., 19901 Multiple epiphyseal dysplasia [Wordsworth et al., 19881 Pseudoachondroplasia [Wordsworth et al., 19881 SED tarda [Wordsworth et al., 19881 SED type Kimberley [Anderson et al., 1990bl Stickler syndrome (some families) [Knowlton et al., 19891 Trichorhinophalangeal syndrome [Wordsworth et al., 19881 TYPE I11 COLLAGEN COL3A1 Gene: alpha 1 chain of type I11 collagen; alpha l(II1) Locus symbol: COL3Al Size: 38 kilobases Chromosomal location: 2q31-32.3 [Huerredeanpierre et al., 19861 Linkage Data Disorders linked to COL3A1: EDS, Type IV variable type I11 collagen [Tsipouras et al., 1986; Nicholls et al., 19881 Disorders not linked to COL3A1: Marfan syndrome [Dalgleish e t al., 1987; Ogilvie et al., 1987; Francomano et al., 19881

OTHER GENE LOCI AND CANDIDATE PROTEINS TYPE I COLLAGEN COLlA2 The following;tables are designed to present informaLocus name: alphaz chain of type I collagen; alpha 2(1) tion about heritable disorders Gf connective tissue and connective tissue biochemistry in which the major colLocus symbol: COLlA2 lagen molecules or elastin are involved. The information Size: 38 kilobases [de Wet et al., 19871 Chromosomal location: 7q22 [Henderson et al., 19831 is organized in 4 categories:

OP OP 01, Type I

Disease

~~

Evidence Increased bone type I11 collagen; increased content of alpha 1(I) trimers Heterozygous Gly(661)to Ser substitution in an alpha 2(I) chain Half normal amounts of alpha l(1) mRNA in fibroblasts

TABLE 11. Provisional Data References Batge et al., 1990 Spotila et al., 1990 Rowe et al., 1985

166210

259400

259420

166220 Hetero

166220

166220

01, Type I1

01, Type I11

01, Type I11

01, Type IV

01, Type IV

01, Type IV

01, lype I1

EDS, 5 P e VIIB EDS, Type VIIB

01, Type I/ EDS (unclassified)

166210

01, Type 11

Hetero

Hetero

130060

166210

Hetero

130060

Hetero

Hetero

Hetero

Homo

Hetero

Homo

Hetero

166210 Hetero

Gly(472) to Cys

Gly(694) to Arg

Gly(907) to Asp

Protein change Residues 209-223 deleted

Residues 73-90 deleted

Gly(646) to Cys

Gly(1012) to Arg

Gly(586) to Val

LMd; s; exon 33 G(5) to A, IVS 33

Residues 667-684 deleted

Residues 1-18 PMm; s; exon 6 G(54) to A deleted PMm; s; exon 6 T(2) Residues 1-18 to C in IVS6 de1eted

PMrn; exon 34 G(2) to T PMm; exon 49 G(38) tOC PMm; exon 37 G(19) to T LMd; s; exon 11 del 19 bp at the junction of IVS 10 and exon 11

PMm; exon 20 G(10) Gly(259) to Cys toA LMd; f; exon 52. Del Alpha(1) trirner 4bp resulting in out-of-frame reading

PMm; exon 44 G(28) Gly(865) to Ser to A PMrn; exon 28 G(28) Gly(457) to Arg toC PMm; s; exon 28 g Residues 548-566 to A at 3' deleted consensus of IVS27

Mutation MIM # Zygosity 166200 Hetero LMd; s; exon 13; IVS 13, del between nt + 4 to + 22 166210 Hetero PMm; exon 45 G(47) to A 166210 Hetero PMm; exon 39 G(1) toA 166210 Hetero PMm; exon 29 G(19) to T

01, Type 11

01, Type I1

01, Type I1

01, Type I1

Disease 01, Type 1

Baldwin et al., 1989

References Zhuang et al., 1990

Comments

N-telopeptide Weil et al., 1988, 1990 Vasan et al., 1991 Ganguly et al., 1990 Helical

Tsuneyoshi et al., 1990 Helical Edwards et al., 1990 The mildly affected parent is mosaic for mutation in the germline and somatic tissues Helical Lamande et al., 1989 Helical Bateman et al., 1990 Helical The proband is a Tromp et al., 1988 compound heterozygote. Other allele is silent. Helical WenstruD et al.. 1990 C-pro peptide Dickson et al., 1984 Parents are Pihlajanierni et al., heterozygous for 1984 the mutation and are phenotypically normal. Helical Bateman et al., 1990 Wenstrup et al., Helical 1988 Wenstrup et al., Helical 1991 Kuivaniemi et al., Significant Helical 1988 variability of expression among affected individuals. Phenotype is a mixture of 01 and mild EDS. N-telopeptide Weil et al., 1989

Helical

Helical

Domain Helical

TABLE 111. COLlA2: Known Mutations

Disease Kniest syndrome SEDc

MIM # 156500 183900

Comments Intron to intron del

References Poole et al., 1988 Murray et al., 1989

Partial exon duplication Helical Ala-Kokko et al., Initially reported as 1990 OA. Now regarded as mild SEDc. Helical Ahmad et al., 1990 Disease linked to Knowlton et al., 1989 COLPAl Helical Vissina et al.. 1989

Helical Tiller et al., 1990

Domain References Helical Lee et al., 1989

Evidence Intracellular retention of the C-propeptide of type I1 collagen Overmodification of type XI collagen and constituent CNBr peptides

TABLE V. Provisional Data

PMm: exon 46 G to A Glv(943) to Ser

200610

Hetero

PMm; exon 39 C to T Arg(732) to STOP

108300 Hetero

Stickler syndrome Ach-HvD

SEDc

SEDc

MIM # Zygosity Mutation Protein Change 183900 Hetero LMd; deletion of exon 36 aa del (exon 48) 48 183900 Hetero LMi; 45 bp ins in 15 aa duplicated exon 48 Arg(519) to Cys 183900 Hetero PMm; exon 31

Disease SEDc

TABLE IV. COL2A1: Known Mutations

PMm; intra-exonic

PMm; intra-exonic

130050 Hetero

Hetero

Hetero

EDS, q p e IV

Arterial aneurysms/ EDS, me IV Arterial aneurysms/ EDS, w e IV

Hetero

LMd; 27 bp in exon 37

130050

EDS, Type IV

Hetero

130050

EDS, Type IV

~

~~

~

~

~

Helical

Helical

Gly(790) to Ser

Helical

Gly(619) to Arg

9 aa deleted

Tromp et al., 1989a Stolle et al., 1985

Nicholls et al., 1988 Narcisi et al., 1989 Richards et al., in press, a Kontusaari et al., 1990a

trimers equally well secreted Heterotrimers retained; collagen cleavage site deleted Variable type I11 collagen Linkage with COL3A1 Moderate joint laxity, minimal skin changes Familial aneurysms Classical, severe EDS IV

Protein change Domain References Comments normal and shortened Helical McGookey et al., 1989 Paternal mosaicism Equal amount protein (10%) of normal/ shortened type I11 collagen LMd; 7.5 kb; exon 9 342 a a deleted aa(46) Helical Superti-Furga et al., Classical EDS IV 1988, 1989 to aa(387) shortenedhormal to intron 24 type 111 collagen Lee et al., 1991a secreted Affected father and son LMd; 9.0 kb intron 33 414 aa deleted Helical Superti-Furga et al., Mild EDS IV 1989 to exon 48 Uncomplicated aa(586) to aa(999) Short pregnancy and long Vissing et al., 1991

MIM # Zvgositv Mutation 130050 Hetero LMd; 2 kb deletion near 5' end

Disease EDS, Type IV

~~~

TABLE VI. COL3A1: Known mutations

130050 Hetero

130050 Hetero

Hetero Hetero

130050 Hetero

130050 Hetero

130050 Hetero

130050 Hetero

EDS, Type IV

EDS, Type IV

EDS, Q p e IV

EDS, Type IV

EDS, Type IV

EDS, Type IV

EDS, Type IV

EDS, Type IV

PMs; IVS 27 + 5 G to T PMs; IVS 25+5 G to T

PMs; IVS42 + 1 splice junction G to A

PMs; IVS41+ 1 splice junction G to A

PMs; IVS20 + 1 splice junction G(1) to A

PMs; IVS16 + 1 splice junction G to A

PMm; intra-exonic

PMm; intra-exonic

Helical

Helical

Helical

Helical

Helical

Helical

Helical

Gly(910) to Val

Mild EDS IV Affected father and daughter De Paepe et al., 1991 Mild EDS IV bowel Richards et al., in perforation press Poor secretion of collagen 111; decreased thermal stability Kuivaniemi et al., Aneurysm of cervical 1990a artery Soft skin Kontusaari et al., Aortic aneurysm 1990b Easy bruisability Kuivaniemi et al., Soft skin 1990 50% normal type I11 collagen Cole et al., 1990 Poor secretion of type I11 collagen Colleganse cleavage site deleted Kuivaniemi et al., Severe EDS 1990 Aortic aneurysm Soft skin Thakker-Varia et al.. 10% type I11 collagen 1990 secreted Superti-Furga et al., Severe, sporadic EDS 1989 IV, decreased Lee et al., 1991b thermal stability, of COLIII temperaturedependent alternative splicing

Helical Tromp et al., 1989b

Gly(883) to Asp

Disease Familial cerebral aneurysms

MIM # Evidence Type 111collagen deficiency in cultured skin fibroblasts in some patients with congenital berry aneurysms

References Pope et al., 1981, Pope, 1989 Pope et al., 1990 Leblanc et al., 1989

TABLE VII. Provisional Data Comments In some patients with cerebral aneurysms normal type I11 collagen levels were present Genetic heterogeneity?

IDS

Xa28

MANB

19~13.2-q.12

FRAXA

G6S FBNl

12q14 15q21.1

Xq27.3

CLG

llqll-23

COL4A5

GUSB

7q21.1-q22

xq22

ARSB FBN2

5qll-q13 5q23-q31

Sulfoiduronate sulfatase

Collagen IV, alpha-5 Barker et al., 1990 Myers et al., 1990 Fragile site Xq27.3 Thibodeau et al., 1988 Sutherland & Baker, 1989

Alpha-L-iduronidase Schuchman et al., 1984

AGA

4q21-qter

IDUA

GNPTA

4q21-q23

22qll

GLB1

3~21-pl42

CBS

Beta-D-galactosidase-1 [2305001 Geihl et al., 1989 N-acetyl-alpha-glucosaminylphosphotransferase Mueller et al., 1987 Aspartylglucosominidase Aula et al., 1984 Arylsulfatase B Fibrillin-like protein Lee et al., 1991 Beta-glucoronidase Allanson et al., 1988 Collagenase Gerhard et al., 1987 N-acetylglucosamine-6-sulfatase Fibrillin Maslen et al., 1991 Alpha-D-mannosidosis B Kaneda et al., 1987 Cystathionine-beta-synthase Skovby et al., 1982, 1948

FN1

2q34-q36

21q22.3

Fibronectin-1 Jhanwar et al., 1986

ELN

FUCAl

lp34

Locus name Alkaline phosphatase [1717601 Chodirker et al., 1987 Alpha-L-fucosidase-1 Fowler et al., 1986 Willems et al., 1988a Elastin

2q31-qter

Symbol ALPL

Map Position lp36.2-~34

Martin-Bell syndrome [3095501 Pyeritz et al., 1982 Hagerman & Synhorst, 1984 Hagerman et al., 1984 Opitz et al., 1984 MPS I1 13092001 (Hunter svndrome)

Homocystinuria [236200] pyridoxine-nonresponsive; pyridoxinresponsive Munke et al., 1988 MPS IH, IH/S. IS [252800] (Hurler, Scheie, & Hurler-Scheie syndromes) Schuchman & Desnick, 1988 Alport syndrome [3010501 Hasstadt and Atkin, 1983

Epidermolssis bullosa dvstrophica, recessive r2266001 'Bauer & Eisen, 1978 MPS IIID r25294oi Marfan syndrome Hollister et al., 1990 Kainulainen et al., 1990 Dietz et al., 1991a,b Lee et al., 1991 Mannosidosis [2485001

MPS VII 12532201

Aspartylglucosaminuria [208400] Mononen et al., 1991 MPS VI [2532001 Congenital contractual arachnodactyly [121050]

Osteopoikilosis 11667001 Berlin et al., 1967 ?ED'S, type X [225310] Arneson et al., 1980 Plasma fibronectin deficiency Shirakami et al., 1986 MPS IVB [253010l(Morquio B) also G,,-gangiosidosis van der Horst et al., 1983 Mucolipidosis 11; mucolipisosis I11 [252500] Ben-Yoseph et al., 1987

Disorderk) assoc. with locus Hypophosphatasia, infantile [241500] Hypophosphatasia, adult [1463001 Fucosidosis [2300001 Willems et al., 1988b

TABLE VIII. Other Gene Loci: Mapped Human Gene Loci for Which Both a Heritable Disorder of Connective Tissue and a Component of the Extracellular Matrix Are Known

442

Beighton et al. TABLE IX. MaDDed Human Phenotwes for Which the Basic Defect is Unknown ~~~~

Map Position

~

Symbol EBS2 AKE DGIl CMDl PDB LGCR EBSl NPSl

lq2 1-q24 2P 4q13-q21 5q33.1 6p21.3 8q23.2-q24.11 8q24 9q34 16~13.31-

PKDl

18 20~11.23-~12.1 Xpter-p22.32 xp22 xp22 xp22.2-p22.1 xq12-q13 Xa28 X428 X

DD AHD CPXR SEDL AIH CLS MNK CPXD MRSD

Disorder(s) assoc. with locus Epidermolysis bullosa simplex, Koebner type [131900] Acrokeratoelastoidosis [1018501 Dentinogenesis imperfecta-1 [1254901 Ball et al., 1982 Campomelic dysplasia with sex reversal [2119701 also 8q21.4 (balanced translocation] Paget disease of bone [1672501 Langer-Giedion syndrome [1502301 Ludecke et al., 1989 Epidermolysis bullosa simplex-1 [131950] Naihatella svndrome r1612001: Renwick & Schulze. 1965: Westerveld et al.. 1976: Puffenberger et al., 1990 -' Adult polycystic kidney disease [173900] Reeders et al., 1985, 1987, 1988; Ryynanen et al., 1987: Watson et al.. 1987: Kimberling et al.. 1988: Bachner et al.. 1989: McParland et al., 1'989 Diastropic dysplasia [222600] Holmgren et al., 1984 Arteriohepatic dysplasia [118450] Byrne et al., 1986; Shrimpton et al., 1989 Chondrodysplasia punctata, recessive [3029501 Bick et al., 1989 Spondyloepiphyseal dysplasia tarda [3134001 Szpiro-Tapia et al., 1988 Amelogenesis imperfecta [301200] [3011001 Lagerstrom et al., 1989 Coffin-Lowry syndrome [303600] Hanauer et al., 1988; Gilgenkrantz et al., 1988 Menkes disease [309400] Tonnesen et al., 1986 Chondrodysplasia punctata, dominant [302960] Mental retardation and skeletal dysplasia [3096201 Occipital horn syndrome [304150] (formerly Ehlers-Danlos syndrome type IX) Byers et al., 1980 Peltonenen et al.. 1983 Storis et al.. 1984

-

TABLE X. Candidate Loci: Mapped Components of the Extracellular Matrix Without Known Phenotwic Associations ~~

Map Position lq31 lq43 2 4 4p14.8-q21 5q31-q33 7011.2 7431.1-q31.3 lop11.2 10a21.3-a23.1 10422.1 llq12.1-q13.5 12P 12~12.1-qter 12qll-ql3 12q11-q21 13q14 13q34 13q34 14 15 15 16q21 17qll-q21 17q25 18~11.31 20 XP Xql3qter

Symbol LAMB2 NID VNRA OPN BMP3 ON ELN LAMB1 FNRB P04HA PRG FNL2 ELAl DCN FNRA KRTA BMPl COL4A1 COL4A2 BMP2A COLlAR CSPGl CLG4A KRTB P4HB LAMA BMP2Bl AMEL BGN

Matrix component assoc. with locus Laminin B2 [1502901 Nidogen (entactin) [1313901 Mattei M-G, 1989 Vibronectin receptor, alpha polypeptide [193210] Osteopontin [166490] Bone morphogenic protein-3 [112263] Osteonectin [1821201 Naylor et al., 1989 Elastin [130160] Fazio et al., 1991 Laminin B1 [1502401 Fibronectin receptor, beta subunit [135630] Prolyl-4-hydroxylase, alpha [176710] Proteoglycan, secretory granule [1770401 Fibronectin-like-2 [135610] Elastase-1 [130120] Decorin [125255] Fibronectin receptor, alpha subunit [135620] Keratin, acid or alpha [139350] Bone morphogenic protein-1 [112264] Alpha 1 (IV) procollagen [1201301 Alpha 2 (IV) procollagen [l200901 Bone morphogenic protein-2a [112261] Collagen I, alpha, receptor [120340] Chondroitin sulfate proteoglycan core protein [1557601 Rettig et al., 1984; Finkelstein et al., 1991 Collagenase type IVA [1203601 Fan Y-S et al., 1989 Keratin, basic or beta [148030] Prolyl-4-hydroxylase, beta subunit [1767901 Laminin A chain [1503201 Mattei M-G et al., 1989 Bone morphogenic protein-2bl [112262] Amelogenin [3012001 Bialscan [3018701

Molecular Nosology of Heritable Connective Tissue Disorders

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TABLE XI. Unmapped Candidate Loci for Components of the Extracellular Matrix Symbol CSPGLP

Locus name Chondroitin sulfate proteoglycan link protein

Disorderb) assoc. with locus Not linked to achondroplasia and pseudoachondroplasia Finkelstein et al., 1991

Collagen galactosyl transferase Collagen glucosyl transferase ELA2

Elastase-2 Lysyl hydroxylase Lysyl oxidase Procollagen C-proteinase Procollagen N-proteinase Prolyl-3-hydroxylase Signal peptidase (procollagen)

0 Mapped human gene loci for which both a heritable disorder of connective tissue and a component of the extracellular matrix are known 0 Mapped human phenotypes for which the basic defect is unknown 0 Candidate loci: mapped components of the extracellular matrix without known phenotypic associations Unmapped candidate loci for components of the extracellular matrix

ACKNOWLEDGMENTS We are grateful to Mrs. S. Thorne for typing the manuscript with enthusiasm and efficiency. We offer our thanks to the Ciba Foundation of London for providing facilities for our meetings and to the Medical Research Council of South Africa, the Mauerberger Foundation, and the University of Cape Town Staff Research Fund for financial support. The European Concerted Action on Heritable Connective Tissue Diseases (project leader, Prof. M. Matton) kindly provided assistance for our Corfu meeting. We are grateful to the following colleagues and their respective co-workers for communications concerning their unpublished observations: Drs. P.H. Byers, W.G. Cole, H. Kuivaniemi, B. Lee, D.J. McGookey, P. Narcisi, A.C. Nicholls, D.J . Prockop, F. Ramirez, A.J. Richards, A. Superti-Furga, and G. “romp. Dr. R.E. Pyeritz was supported by grant HL35877 from the National Institutes of Health (REP) USA. Dr. P. Tsipouras received support from the Coles Family Foundation. REFERENCES Introduction Beighton P, de Paepe A, Danks D, Finidori G, Gedde-Dahl T, Goodman R, Hall JG, Hollister DW, Horton W, McKusick,VA, Opitz JM, Pope FM, Pyeritz RE, Rimoin DL, Sillence D, Spranger JW, Thompson E, Tsipouras P, Viljoen D, Winship I, Young I (1988): International nosology of heritable disorders of connective tissue, Berlin, 1986. Am J Med Gen 29581-594. McKusick VA (1990): “Mendelian Inheritance in Man,” 9th ed. Baltimore: Johns Hopkins University Press.

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EDS VI [225400] EDS VII [225410]

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COL3A1 Cole WG, Chiodo AA, Lamande SR, Janeczko, Ramirez F, Dahl H-HM, Chan D, Bateman JF (1990):A base substitution a t a splice site in the COL3A1 gene causes exon skipping and generates abnormal type 111procollagen in a patient with Ehlers-Danlos syndrome type IV. J Biol Chem 265:1700-1707. Dalgleish R, Hawkins JR, Keston M (1987):Exclusion of the alpha 2(I) and alpha l(II1) collagen genes as the mutant loci in a Marfan syndrome family. J Med Genet 24:148-151. De Paepe A, Nuytinck L, Nicholls AC, Narcisi P, de Roose J , Matton M (1990): Study of a type 111collagen protein defect in a patient with ecchymotic EDS: Importance of the analysis of non-cutaneous connective tissues. In Bartsocas C, Loukopoulos D (eds): “Genetics of Hematological Disorders.” Washington D.C.: Hemisphere Publishing Corporation, in press. Francomano CA, Streeten FA, Myers DA, Pyeritz RE (1988): Marfan syndrome: Exclusion of genetic linkage to three major collagen genes. Am J Med Genet 29:451-662.

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Huerre-Jeanpierre C, Mattei MC, Weil D, Grzeschik KH, Chu ML, Sangiorgi FO, Sobel ME, Ramirez F, Junien C (1986): Further evidence for the dispersion of the human fibrillar collagen genes. Am J Hum Genet 38:26-27. Kontusaari S, Tromp G, Kuivaniemi H, Romaine A, Prockop DJ (1990a): A mutation in the gene for type I11 procollagen in a family with aortic aneurysms. J Clin Investigation 86:1465-1469. Kontusaari S, Tromp G, Kuivaniemi H, Ladda RL, Prockop DJ (1990b): Inheritance of an RNA splicing mutation (G + 1,IVS 20) in the type 111procollagen gene (COL3A1)in a family having aortic aneurysms and easy bruisability: Phenotypic overlap between familial arterial aneurysms and Ehlers-Danlos syndrome type IV. Am J Hum Genet 47:112-120. Xuivaniemi H, Kontusaari S, Tromp G, Zhao M, Sabol C, Prockop DJ (1990): Identical G + 1to A mutations in three different introns of the type I11 procollagen gene (COL3A1)produce different patters of RNA splicing in three variants of Ehlers-Danlos syndrome IV (1990). An explanation for exon skipping with some mutations and not others. J Biol Chem 2651206-1207. Leblanc R, Lozano AM, van der Fkst M, Guttmann RD (1989):Absence of collagen deficiency in familial cerebral aneurysms. J Neurosurg 70037-840. Lee B, DAlessio M, Vissing H, Ramirez F, Steinmann B, Superti-Furga A (1991a): Characterization of a large genomic deletion associated with a polymorphic block of repeated dinucleotides in the type I11 procollagen gene (COL3A1) of a patient with Ehlers-Danlos syndrome type IV. Am J Hum Genet 48511-517. Lee B, Vitale E, Superti-Furga A, Steinmann B, Ramirez F (1991b): G to T transversion at position + 5 of a splice donor site causes skipping of the preceding exon in the type I11procollagen transcriptsof a patient with Ehlers-Danlos syndrome type IV. J Biol Chem 2665256-5259. McGookey DJ, Smith ACM, Waldstein G, Byers PH (1989): Mosaicism for a deletion in one of the type I11collagen alleles indicates that the deletion occurred after identification of cells for recruitment in different cell lineages early in human development. Am J Hum Genet 45:A206 (abstract). Narcisi P, Nicholls AC, De Paepe A, Pope FM (1989): An alpha l(1III) CB5 mutation in Ehlers-Danlos syndrome type IV. J Med Genet 26:211 (abstract). Nicholls AC, De Paepe A, Narcisi P, Dalgleish R, De Keyser F, Matton M, Pope FM (1988): Linkage of a polymorphic marker for the type I11 collagen gene (COL3A1) to atypical autosomal dominant EhlersDanlos syndrome type IV in a large Belgian pedigree. Hum Genet 78:276-281. Ogilvie DJ, Wordsworth BP, Priestley LN, Dalgleish R, Schmidtke J , Zoll B, Sykes BC (1987): Segregation of all four major fibrillar collagen genes in the Marfan syndrome. Am J Med Genet 41:10711082. Pope FM, Narcisi P, Neil-Dwyer G, Nicholls AC, Bartlett J , Doshi B (1981):Some patients with cerebral aneurysms are deficient in type I11 collagen. Lancet 1:973-975. Pope FM (1989): Q p e I11 collagen mutations and cerebral aneurysms, Stroke 20:1432. Pope FM, Limburg M, Schievink WI (1990): Familial cerebral aneurysms and type 111 collagen deficiency. J Neurosurg 72:156-157. Richards AJ, Lloyd JC, Narcisi P, Nicholls AC, Ward PN, De Paepe A, Pope FM. A 27bp deletion from one allele of the type 111 collagen gene Col 3A1 in a large family with atypical Ehlers Danlos Syndrome type IV. Hum Genet, in press. Richards AJ, Lloyd JC, Ward PN, De Paepe A, Narcisi P, Pope FM (1991): Characterisation of a glycine to valine substitution at aminoacid position 910 of the triple helical region of type I11collagen in a patient with Ehlers Danlos Syndrome type IV. J Med Genet, in press. Stolle CA, Pyeritz R, Myers GC,Prockop DJ (1985): Synthesis of an altered type I11 procollagen in a patient with type IV EDS. J Biol Chem 260:1937-1944. Superti-Furga A, Gugler, E, Gitzelmann R, Steinmann B (1988): Ehlers-Danlos syndrome type IV: A multi-exon deletion in one of the two COL3A1 alleles affecting structure, stability, and processing of type I11 procollagen. J Biol Chem 2635226-6232. Superti-Furga A, Steinmann B, Ramirez F, Byers PH (1989):Molecular defects of type 111 collagen in Ehlers-Danlos syndrome type IV. Hum Genet 82:104-108.

Superti-Furga A, Lee B, DAlessio M, Steinmann B, Ramirez F (1990): Identification of a highly polymorphic (CA)n(TA)n(GT)nelement in intron 24 of the COL3A1 gene, Matrix 10:249-250. Thakker-Varia S, Anderson D, Kuivaniemi H, Tromp G, Prockop DJ, Stolle CA (1990): An exon deletion in type 111procollagen mRNA is associated with intracellular degradation of the abnormal protein in a patient with Ehlers-Danlos syndrome IV. Matrix 10:249-250 (abstract). Tromp G, Kuivaniemi H, Shikata H, Prockop DJ (1989a): A single base mutation that substitutes serine for glycine 790 of the alpha l(1II) chain of type I11 procollagen exposes an arginine and causes EhlersDanlos syndrome IV. J Biol Chem 264:1349-1352. Tromp G, Kuivaniemi H, Stolle C, Pope FM, Prockop D (1989b): Single base mutation in the type I11 procollagen gene that converts the codon for glycine 883 to aspartate in amildvariant of Ehlers-Danlos syndrome IV. J Biol Chem 264:19313-19317. Tsipouras P, Byers PH, Schwartz RC, Chu ML, Weil D, Pepe D, Cassidy SB, Ramirez F (1986): Ehlers-Danlos syndrome type IV:Cosegregation of the phenotype to a COL3A1 allele of type I11 procollagen. Hum Genet 74:41-46. Vissing H, D'Alessio M, Lee B, Ramirez F, Byers PH, Steinmann B, Superti-Furga A (1991): Multi-exon deletion in the procollagen I11 gene is associated with mild Ehlers-Danlos syndrome type IV. J Biol Chem 266:5244-5248.

Other Gene Loci and Candidate Proteins Allanson J E , Gemmill RM, Hecht RK, Johsen S, Wenger DA (1988): Deletion mapping of the beta-glucuronidase gene. Am J Med Genet 29517-522. Arneson MA, Hammerschmidt DE, Furcht LT, King RA (1980): A new form of Ehlers-Danlos syndrome: Fibronectin corrects defective platelet function. JAMA 244:144-147. Aula P, Astin KH, Francke U, Desnick R J (1984): Assignment of the structural gene encoding human aspartylglucosaminidase to the long arm of chromosome 4 (4q21-4qter).Am J Hum Genet 36:12151224. Bachner L, Vinet MC, Lacave R, Sraer JD, Chevet D, Julier C, Kaplan J C (1989): Linkage analysis of a French family with autosomal dominant polycystic kidney disease (ADPKD) non allelic to PKDl locus. HGMlO Abstracts: 148. Bachner L, Vinet MC, Albouze G, Julier C, Le Merrer M, Kaplan J , Mathiew M, Piussan C, Grunfeld JP, Kaplan J C (1989): Linkage analysis of 15French families with various clinical forms of autosoma1 dominant polycystic kidney disease (ADPKD). HGMlO Abstracts: 149. Ball SP, Cook PJL, Mars M, Buckton KE (1982): Linkage between dentinogenesis imperfecta and Gc. Ann Hum Genet 46:35-40. Barker DF, Hostikka SL, Zhou J , Chow LT, Oliphant AR, Gerken SC, Gregory MC, Skolnick MH, Atkin CL, "ryggvason K (1990): Identification of mutations in COL4A5 collagen gen in Alport syndrome. Science 248:1224-1227. Bauer EA, Eisen AZ (1978): Recessive dystrophic epidermolysis bullosa: Evidence for increased collagenase as a genetic characteristic in cell culture. J Exp Med 148:1378-1387. Ben-Yoseph Y, Potier M, Mitchell DA, Pack BA, Malancon GB, Nadler H (1987): Altered molecular size of N-acetylglucosamine l-phosphotransferase in T-cell disease and pseudo-Hurler polydystrophy. Biochem J 248697-701. Berlin R, Hedensin R, Lilja R, Linder L (1967): Osteopoikilosiga clinical and genetic study. Acta Med Scand 181:305-314. Bick DP, Snead ML, Yen PH, McGill JR, Schorderet DG, Hejtmancik JF, Ballabio A, Campbell L, Moore CM, Curry CJ, Lau EC, Sbapiro LJ (1989): Mapping chondrodysplasia punctata, ichthyosis, Kallmann syndrome and DNA markers in male patients with Xp chromosome deletions. HGMlO Abstracts: 32. Byers PH, Siege1RC, Holbrook KA, Narayanan AS, Bornstein P, Hall J G (1980): X-linked cutis laxa. N Engl J Med 30361-65. Byrne JLB, Harod MJE, Friedman JM, Howard-Peebles PN (1986): del (20p) with manifestations of arteriohepatic dysplasia. Am J Med Genet 24:673-678. Chodirker BN, Evans JA, Lewis M, Coghlan G, Belcher E, Philipps S, Seargeant LE, Sus C, Greenberg CR (1987): Infantile hypophosphatasia-linkage with the RH locus. Genomics 1:280-282.

Molecular Nosology of Heritable Connective Tissue Disorders Curry CJR, Magenis RE, Brown M, Lanman J T Jr., Tsai J , OLague P, Goodfellow P, Mohandas T, Bergner EA, Shapiro LJ (1984): Inherited chondrodysplasia punctata due to a deletion of the terminal short arm of an X chromosome. N Engl J Med 311:lOlO-1015. Dietz HC, Pyeritz RD, Hall BE, Cadle RG, Hamosh A, Schwartz J , Meyers DA, Francomano CA (1991): The Marfan syndrome locus: Confirmation of assignment to chromosome 15 and identification of tightly linked markers at 15q15-q21.3. Genomics, in press. Dietz HC, Cutting GR, Pyeritz RE, Maslen CL, Sakai LY, Corson GM, Puffenberger EG, Hamosh A, Nanthakumar EJ, Curristin SM, Stetten G, Meyers DA, Francomano CA (1991b): Defects in the fibrillin gene cause the Marfan syndrome: Linkage evidence and identification of a missense mutation. Nature, in press. Fan Y-S, Eddy RL, Hyhtala P, Byers MG, Haley LL, Henry WM, lkyggvason K, Shows TB (1989): Collagenase type IV (CLG4) is mapped to human chromosome 16q21. HGMlO Abstracts: 79. Fazio MJ, Mattei M-G, Passage E, Chu M-L, Black D, Solomon E, Davidson JM, Uitto J (1991):Human elastin gene: New evidence for localization to the long arm of chromosome 7. Am J Hum Genet 48~696-703. Finkelstein JE, Doege K, Yamada Y, Pyeritz RE, Graham JM, Moeschler JB, Francomano CA (1990): Analysis of chondroitin sulfate proteoglycan core protein (CSPGCP) and link protein (CSPGLP)gene in achondroplasia and pseudoachondroplasia.Am J Hum Genet 48:97-102. Fowler ML, Nakai H, Byers MG, Fukushima H, Eddy RL, Henry WM, Haley LL, O’BrienJS, ShowsTB (1986):Chromosome 1localization of the human alpha-L-fucosidase structural gene with a homologous site on chromosome 2. Cytogenet Cell Gent 43:103-108. Gal A, Wirth B, Kaariainen H, Lucotte G, Landaia P, GillessenKaesbach G, Muller Wiefel DE, Zerres K (1989): Childhood manifestation of autosomal dominant polycystic kidney disease: No evidence for genetic heterogeneity. Clin Genet 3513-19. Geihl D, Mudd M, O’Brien J, Yamamoto Y, Naylor SL (1989):Regional mapping of the human beta-galactosidase gene using a cDNA probe. HGMlO Abstracts: 47. Gerhard DS, Jones C, Bauer FA, Eisen AZ, Goldberg GI (1987):Human collagenase gene is localized to l l q . Cytogenet Cell Genet 46:619 (Abstract). Gilgenkrantz S,Mujica P, Gruet P, Tridon P, Schweitzer F, NivelonChevalilier A, Nivelon JL, Couillault G, David A, Verloes A, Lambotte C, Piussan C, Mathieu M (1988): Coffin-Lowry syndrome: A multicenter study. Clin Genet 34:30-245. Hagerman RJ, Synhorst DP (1984): Mitral valve prolapse and aortic dilatation in the fragile X syndrome. Am J Med Genet 17:123-131. Hagerman FLJ, Van Housen K, Smith ACM, McGavran L (1984): Consideration of connective tissue dysfunction in the fragile X syndrome. Am J Med Genet 17:111-121. Hanauer A, Alembik Y, Gilgenkrantz S, Mujica P, Nivelon-Chevallier A, Pembrey ME, Young ID, Mandel J L (1988):Probable localisation of the Coffin-Lowry locus in Xp22.2-p22.1 by multipoint linkage analysis. Am J Med Genet 30:523-530. Hasstedt SI, Atkin CL (1983): X-linked inheritance of Alport syndrome: Family P revisited. Am J Hum Genet 351241-1251. Hollister DW, Godfrey M, Sakai LY, Pyeritz RE (1990): Immunohistologic abnormalities of the microfibrillar-fiber System in the Marfan syndrome. N Engl J Med 323:152-159. Holmgren G, Jagell S, Lagekvist B, Nordenson I (1984): A pair of siblings with diastrophic dysplasia and E trisomy mosaicism. Hum Hered 34:266-268. Jhanwar SC, Jensen JT, Kaelbling M, Chaganti RSK, Klinger HP (1986): In situ localization of human fibronectin (FN) genes to chromosome regions 2~14-~16,2q34-q36, and llq12.1-q13.5 in germ line cells, but to chromosome 2 sites only somatic cells. Cytogenet Cell Genet 41:47-53. Kainulainen K, F’ulkkiner L, Savolainen A, Kaitila I, Peltonen L (1990): Location on chromosome 15 of the gene defect causing Marfan syndrome. N Engl J Med 323:935-939. Kaneda Y, Hayes H, Uchida T, Yoshida MC, Okada Y (1987):Regional assignment of five genes on human chromosome 19. Chromosoma 958-12. Kimberline WJ. Fain PR. Kenvon JB. Goldgar D, Suianskv E, Gabow PA (198u8):Linkage heterogeneityof autosoma1 dbminant polycystic kidney disease N Engl J Med 319:913-918. I

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