Novel Insights from Clinical Practice

HOR MON E RE SE ARCH I N PÆDIATRIC S

Horm Res Paediatr 2014;82:206–212 DOI: 10.1159/000362618

Received: November 5, 2013 Accepted: April 1, 2014 Published online: July 23, 2014

Identification of a Novel Nonsense Mutation in the Ligand-Binding Domain of the Vitamin D Receptor Gene and Clinical Description of Two Greek Patients with Hereditary Vitamin D-Resistant Rickets and Alopecia Anna Papadopoulou a Evangelia Bountouvi a Evangelia Gole a Artemis Doulgeraki b Symeon Tournis c Anastasios Papadimitriou a Polyxeni Nicolaidou a a

Third Department of Pediatrics, Athens University Medical School, ‘Attikon’ University General Hospital, Department of Bone and Mineral Metabolism, Institute of Child Health, ‘Agia Sophia’ Children’s Hospital, and c Research Laboratory of the Musculoskeletal System ‘Th. Garofalidis’, University of Athens, ‘KAT’ Hospital, Athens, Greece b

Established Facts • Hereditary vitamin D-resistant rickets (HVDRR) is a rare autosomal recessive disorder caused by mutations in the vitamin D receptor (VDR) gene. • The type of VDR mutation is associated with the severity of the syndrome and the patient’s response to treatment. • Current therapy consists of oral administration of calcium in association with vitamin D derivates as well as intravenous calcium in more severe cases.

Novel Insights

Key Words Hereditary vitamin D-resistant rickets · Vitamin D receptor · 1,25-Dihydroxyvitamin D · Nonsense mutation · Hormone resistance

© 2014 S. Karger AG, Basel 1663–2818/14/0823–0206$39.50/0 E-Mail [email protected] www.karger.com/hrp

Abstract Background/Aims: We analyzed the vitamin D receptor (VDR) gene in 2 Greek patients who exhibited the classical features of hereditary vitamin D-resistant rickets (HVDRR) type II, including severe bone deformities and alopecia. We also describe the clinical phenotypes and the response to

Anna Papadopoulou, DEA, PhD Third Department of Pediatrics Athens University Medical School, ‘Attikon’ University General Hospital 1 Rimini Street, Haidari, GR–12464 Athens (Greece) E-Mail anpapado @ med.uoa.gr

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• This report describes a novel nonsense mutation (Gln356stop) identified in 2 Greek patients with HVDRR. • The report highlights the impact of the type of VDR mutation in the presence of alopecia in HVDRR patients. • Furthermore, the report documents the positive response of the patients to oral therapy despite the severity of the disease.

© 2014 S. Karger AG, Basel

Introduction

Hereditary vitamin D-resistant rickets (HVDRR) is a rare autosomal recessive disorder caused by altered or null function of the vitamin D receptor (VDR) [1]. The VDR is expressed in many tissues in the human body and mediates the pleiotropic actions of 1,25-dihydroxyvitamin D [1,25(OH)2D], the hormonally active form of vitamin D [2, 3]. HVDRR patients carry homozygous or compound heterozygous inactivating mutations in the VDR gene, thus leading to impaired end-organ responsiveness to the action of 1,25(OH)2D. The resistance of target tissues has been established to range from partial to generalized, mirroring both the heterogeneity of identified mutations and the diverse response to the therapeutic regimens [4]. The altered biochemical profile seen in HVDRR patients includes hypocalcemia, hypophosphatemia, secondary hyperparathyroidism and elevated serum 1,25(OH)2D and alkaline phosphatase (ALP). Impaired function of VDR in the intestine leads to decreased calcium absorption, reduced calcium uptake into the circulation and hypocalcemia. The established hypocalcemia by itself signals a sequence of biological compensatory mechanisms including the increase of parathyroid hormone (PTH; secondary hyperparathyroidism), which in turn increases phosphorus loss in urine and stimulates 1α-hydroxylase to produce more 1,25(OH)2D [5]. The clinical phenotype of HVDRR patients comprises growth retardation, tooth enamel hypoplasia, typical bone deformities such as bowed legs and rachitic rosary. Alopecia is also a common, early feature of the disease, presenting Two HVDRR Patients with a Novel Nonsense Mutation in the VDR Gene

with a clinical spectrum that ranges from skin lesions and sparse hair to total scalp and body nonscarring alopecia, including eyelashes and eyebrows [6]. Exceedingly high levels of serum 1,25(OH)2D and occasionally alopecia are the hallmarks of the disease, distinguishing it from rickets due to 1α-hydroxylase deficiency. Several mutations, at least 48, have been identified throughout the coding region of the VDR gene – most of them missense and nonsense and to a lesser extent splice site mutations and partial (or single) nucleotide deletions – leading to a nonfunctional VDR [1, 7–15]. The human VDR protein consists of 427 amino acids organized in two distinguishable functional domains, the Nterminal DNA-binding domain (DBD) and the C-terminal ligand-binding domain (LBD), separated by a hinge region. Once the cognate interface of LBD is occupied by 1,25(OH)2D conformational changes are induced, enabling the heterodimerization of VDR with the retinoid X receptor (RXR). The unit ligand VDR/RXR modulates the recruitment of coactivators or corepressors required for transcription of the VDR-responsive genes. Mutations localized in the DBD domain seem to correlate with a more severe phenotype and alopecia, while a more variable phenotype is reported for altered LBD. Generally, the response of the patients to treatment is tightly related to the severity of the syndrome, the age of onset and the time of introduction to treatment [4]. We report, here, a novel nonsense mutation identified in the VDR gene in 2 new HVDRR patients, a 6-year-old girl and a 27-year-old woman. The mutation resulted in a truncated VDR (missing part of the LBD) and the patients manifested severe bone deformities and alopecia at the time of diagnosis. Both shared the same origin without any known consanguinity. The clinical features of the patients as well as the treatment introduced are also discussed.

Description of Cases Patient 1, a 6-year-old girl of Greek descent, was admitted to our department because of severe bone deformities, muscle weakness and alopecia (fig. 1). She was a healthy full-term neonate born to phenotypically healthy parents after an uneventful pregnancy and normal spontaneous vaginal delivery with birth weight of 3 kg (30th percentile), length of 50 cm (68th percentile) and head circumference of 34.5 cm (70th percentile). Both perinatal and postnatal histories were without complications. The parents had no known family history of bone disease, alopecia or other genetic disorder but they shared common origin from an urban Greek region. At 3 months of age the child exhibited partial (which gradually extended to total) alopecia and scant eyelashes. She was evaluated by several dermatologists, but no diagnosis was established at

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treatment of our patients. Methods: Genomic DNA was extracted from peripheral blood samples of both patients. Coding region and flanking introns of VDR gDNA was amplified and direct sequenced. Results: A unique cytosine to thymine (C>T) transition was identified at nucleotide position 1066 (c.1066C>T) in the ligand-binding domain of the VDR gene of both patients, predicting the substitution of a glutamine to a terminal codon at position 356 (Gln356stop). Conclusions: The novel nonsense mutation c.1066C>T (Gln356stop) is expected to result in a VDR protein 71 amino acids shorter and thus to affect the normal VDR function. In particular, the missing protein part alters the VDR heterodimerization with the retinoid X receptor which has been correlated with the presence of alopecia. Both patients were introduced to treatment with supraphysiological doses of 1α-calcidiol which improved their clinical phenotypes except for alopecia.

Fig. 2. Radiological findings: legs at 6 years of age, showing ‘wind-

Fig. 1. Photograph of the younger patient, showing bone deformi-

ties and alopecia.

that time. Although she was able to sit without support at 6 months of age, she walked late – at 17 months. By that time medical attention was sought for bowing knees by the parents. Radiological findings in wrists and legs were compatible with rickets. Several laboratory measurements until the age of 6 years repeatedly revealed hypophosphatemia (2.9–3.8 mg/dl), normal serum total Ca (8.9– 9.5 mg/dl) and elevated levels of serum ALP (500–1,676 IU/l), PTH (156–228 pg/ml) and 1,25(ΟΗ)2D (79–120 pg/ml). Serum 25(OH)D levels were between 4.5 and 20 ng/ml. Based on the above laboratory findings and despite the presence of alopecia, nutritional rickets was suspected. Subsequently, the child was introduced to a therapeutic regimen that included vitamin D in 600– 2,000 IU and 1–1.5 μg 1α-calcidiol daily. However, poor response to the treatment prompted referral to our department for further investigation.

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On admission to our service, the child presented with typical clinical signs of rickets: bowing of the thighs, widened wrist and ankle joints, ‘wind-swept’ deformity of lower extremities and total alopecia. Physical examination showed a weight of 30.7 kg (99th percentile), a height of 114 cm (57th percentile) and a head circumference of 52 cm (50th percentile). Rachitic deformities were clinically obvious, while radiological typical findings of rickets were also present (fig. 2). Kidneys were of normal size (assessed by ultrasound) and Ca/creatinine ratio in urine was normal. Laboratory investigation revealed normocalcemia (9 mg/dl), normophosphatemia (4.1 mg/dl), increased ALP (454 IU/l), increased PTH (145.3 pg/ml) and low serum 25(OH)D (14.7 pg/ml). The above serum profile in combination with the severe bone deformities and the presence of alopecia suggested the diagnosis of HVDRR which was further confirmed through molecular study of the VDR gene. The patient was introduced to treatment with oral drops of 1α-calcidiol at an initial dose of 0.1 μg/kg/day since her admission. The dose was progressively increased to 0.6 μg/kg/day (at the time of submission of the article). The child is being closely followed up and the therapeutic approach is to be adjusted according to her clinical and biochemical course. Corrective bone surgery of lower extremities is being planned. Patient 2, a 27-year-old woman, was diagnosed with HVDRR at the age of 2.5 years by our team. She presented with alopecia at 40 days of age and at 18 months bowing of lower extremities was obvious. Classical findings of rickets (diffused osteopenia, rachitic rosary and metaphyseal changes) were depicted on the X-rays. The patient was introduced at 2.5 years of age to oral therapy with 1α-calcidiol (1.1 μg daily). Since then and until her adulthood the patient has been followed-up at another pediatric department in Greece. According to her medical history, she reported normal menses and menarche at 12 years of age. Dental caries was also noticed during childhood. As far as we have been informed, bio-

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swept’ deformity of lower extremities.

Color version available online

Fig. 3. Sequencing of the VDR gene showing the c.1066C>T substitution in exon 9: (1) patient (homozygous), (2) mother (heterozygous) and (3) father (heterozygous).

chemical evaluation at around 4–6 years of age revealed hypocalcemia (8–8.7 mg/dl), hypophosphatemia (3–4.2 mg/dl) and elevated levels of serum ALP (361–1,250 IU/l). Kidney ultrasound was normal and hypercalciuria was absent. Due to poor clinical, radiological and biochemical response, 1α-calcidiol was gradually increased up to 6 μg daily, whereas oral Ca was added to the therapeutic regimen. Thereafter, she underwent 4 corrective osteotomies at the ages of 15, 17, 18 and 24 years, respectively. At the present time the patient is being followed at the Metabolic Bone Disease Department of the ‘KAT’ Hospital. She is under therapy (15 μg of 1α-calcidiol and 2 chewable tablets Calcioral D3 daily) and exhibits a normal serum chemistry panel. She was referred to our hospital at her current age in order to perform the genetic analysis for HVDRR. The family denies consanguinity and ignores common ancestry with our first patient. Written informed consent was obtained from patient 2 and the parents of patient 1 and the study was approved by the ‘Attikon’ University General Hospital institutional review board. Genomic DNA was isolated from peripheral blood samples using the GFX Genomic Blood DNA Purification kit (Amersham, Biosciences). Investigation for mutations within the coding region (exons 2–9) and flanking introns of the VDR gene was performed by PCR and direct sequencing of PCR products at the research laboratory of the Third Department of Pediatrics as previously described [16, 17], with some modifications. Briefly, the samples were cycled for 30 s at 94 ° C, 30 s at the appropriate (for each fragment) annealing temperature and 30 s at 72 ° C for 35 cycles. The primers used in the PCR and sequencing reactions were as follows: exon 2a, 5′-AGCTGGCCCTGGCACTGACTCTGCTCT-3′; exon 2b, 5′-ATGGAAACACCTTGCTTCTTCTCCCTC-3′; exon 3a, 5′-TGCCCAGCCTAGAGGTGAGA-3′; exon 3b, 5′-GACTTCCAGCTGCCCTGTCA-3′; exon 4a, CCTCCTGACTCCCCTTCC-3′; exon 4b 5′-CTCCCAGCAGGCAGACATAC-3′; exon 5a, 5′-CCTGGCACTGGGAGGCTTCG-3′; exon 5b, 5′-CGCCCCCGCTCCCTTACTCT-3′; exon 6a, 5′-CTCTGCTGCCAGGGCACACC-3′; exon 6b, 5′-TGGTGGATGAGTGATCTCCAACCCT-3′; exon 7a,

5′-TGATTTGTGTGGCTTGAAGG-3′; exon 7b, 5′-AAAAAGACTCCCCAGGAGGT-3′; exon 8a, 5′-CTGGCCATTGTCTCTCACAG-3′; exon 8b, 5′-TGCTACGTCTCCCTTCAGGT-3′; exon 9a, 5′-TGAGAGCTCCTGTGCCTTCT-3′, and exon 9b, 5′-AGGAAAGGGGTTAGGTTGGA-3′. Analysis of the VDR gene of both patients revealed a homozygous nonsense mutation in exon 9. In particular, a unique cytosine to thymine (C>T) transition was found at nucleotide position 1066 (c.1066C>T), predicting a Gln356stop substitution (not yet described). The parents of patient 1 were heterozygous for this substitution. The parents of patient 2 were not tested (fig. 3). The premature termination of the translation leads to a protein of 356 instead of 427 amino acids. The nontranslated region codes for part of the LBD domain and the transactivation domain AF2. The FokI polymorphism was absent in patient 1 as well as in her parents (protein translation initiates from the second ATG site). The TaqI polymorphism was absent in patient 1 and her mother, whereas the father was heterozygous regarding this polymorphism. The FokI and TaqI polymorphisms were also absent in patient 2. Her parents were not tested.

Two HVDRR Patients with a Novel Nonsense Mutation in the VDR Gene

Horm Res Paediatr 2014;82:206–212 DOI: 10.1159/000362618

 

 

 

In the present study we report a novel nonsense mutation, c.1066C>T (Gln356X), leading to a premature termination of the VDR protein. The mutation resides in the LBD of the VDR gene and the formed protein misses the last 71 amino acids of the C-terminal protein domain. The genetic deficit was confirmed, in heterozygous form, in the parents of the younger patient who were phenotypically healthy without alopecia or any other known metabolic bone disease. Both patients presented with se209

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Discussion

Exon

Protein

Alopecia

References

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

4 deleted 4 4 4 5 5 6 6 6 6 7 7 7 7 7 7 7 8

p.Glu92fs p.Gln152X p.Lys141-Thr142delinsLWA p.Ile146Thr p.Arg154Cys p.Cys190Trp p.Leu233fs p.Leu227Pro p.Lys240Arg p.Phe251Cys p.Gln259Pro p.Gln259Glu p.Leu263Arg p.Ile268Thr p.Arg271Leu p.Arg274His p.Trp286Arg p.Tyr292X

Yes Yes No No No Yes Yes No Yes Yes Yes Yes Yes No No Νο No Yes

19 20 21 22 23 24 25 26 27 28 29 30

8 8 8 8 8 8 8 deleted 9 9 9 9 9

p.His305Gln p.Ile314Ser p.Gln317X p.Gly319Val p.Gly329Lys p.Val346Met

No No Yes Yes Yes Yes Yes partial Yes Yes No No No

Hawa et al. [32], 1996 Kristansson et al. [26], 1993 Malloy et al. [33], 2004 Song et al. [11], 2011 Song et al. [11], 2011 Thompson et al. [34], 1991 Cockerill et al. [22], 1997 Huang et al. [12], 2012 Kanakanami et al. [7], 2010 Malloy et al. [23], 2001 Cockerill et al. [22], 1997 Macedo et al. [13], 2008 Nguyen et al. [21], 2006 Malloy et al. [35], 2004 Kristansson et al. [26], 1993 Aljubeh et al. [36], 2011 Nguyen et al. [20], 2002 Ritchie et al. [37], 1989 Malloy et al. [38], 1990 Malloy et al. [19], 1997 Whitfield et al. [18], 1996 Malloy et al. [39], 2002 Macedo et al. [13], 2008 Miller et al. [24], 2001 Arita et al. [25], 2008 Ma et al. [14], 2009 Nguyen et al. [21], 2006 Whitfield et al. [18], 1996 Malloy et al. [27], 2007 Malloy et al. [28], 2002 Malloy et al. [40], 2011

p.Arg391Ser p.Arg391Cys p.Tyr401X p.Glu420Lys p.Glu420Ala

vere rickets, total alopecia and high levels of serum 1,25(OH)2D. Although both families ignore any common ancestry, the fact that they share a common geographical origin (two close small villages with a few inhabitants) strengthens the hypothesis of a founder effect which could be further demonstrated by microsatellite analysis. Taken together, the loss of the last part of the VDR protein is responsible for the malfunction of the VDR and consequently for the establishment of the HVDRR phenotype in our patients. Approximately 100 HVDRR cases have been described so far, sharing 48 different mutations [1, 7–15]. Several efforts have been made to design a well-defined correlation between the genotype and the phenotype of the patients using criteria such as the site of the mutation in the gene and the severity of the syndrome, the presence of alopecia or the successful response to treatment [18–20]. Although defects in the DBD have been associated with resistance to 210

Horm Res Paediatr 2014;82:206–212 DOI: 10.1159/000362618

treatment and alopecia [1], patients with mutations in the LBD present a more variable phenotype. This is possibly reflecting the conformational and functional complexity of this domain. Indeed, functional analyses of mutated VDR LBD have shown that defects in this protein region may affect adequate protein expression, the heterodimerization process or the VDR affinity to ligand or coactivators. Alopecia has been suggested to be associated with mutations in LBD subregions which are essential for the heterodimerization with RXR [7, 18, 21–23] and is generally related to severe hormone resistance [1]. Furthermore, treatments may correct the serum biochemical profile and heal the rickets, with no significant change in the hair development. Cumulative data obtained from several scientific groups in the last years have dissociated alopecia from calcium or vitamin D deprivation in rickets [6]. The molecular defect observed in our patients resides in the subregion of the LBD that affects the normal hetPapadopoulou et al.

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Table 1. LBD reported mutations in HVDRR patients

erodimerization with RXR (helices H9, H10 and an E1 domain, which overlaps H4 and H5). A total of 30 different mutations have been reported so far in the LBD (table 1) [4]. Among them, missense mutations that change the normal amino acids 240–263 [7, 13, 21–23] or 319– 391 [13, 18, 21, 24, 25] were associated with alopecia. These regions are considered essential for the RXR heterodimerization [1]. Moreover, functional analyses of the VDR in patients with mutations in the amino acids Arg274Leu, His305Gln, Ile314Ser and Trp286Arg [18– 20, 26] demonstrated significant reduction in the VDR binding affinity to 1,25(OH)2D. However, those patients did not present alopecia. Furthermore, among all nonsense mutations, the p.Y401X led to defective VDR and rickets but not to alopecia. This mutation results in a truncated protein, from which part of the C-terminal domain as well as the whole AF2 domain (essential for the binding of the coactivators) are eliminated [27]. These findings suggest a critical role of an ‘unliganded VDR’ in the hair cycle regulation [28, 29]. Severe hormone resistance is common in HVDRR patients with mutations in the DBD domain whereas altered LBD is associated with variable response to treatment [1]. Our older patient showed an improvement in her biochemical profile around 3 years after the administration of supraphysiological doses of 1α-calcidiol and oral calcium. Although she was introduced early to treatment (2.5 years of age), she needed 4 surgical interventions to achieve a normal skeletal growth. Currently, she has a normal biochemical profile, as seen by serum Ca, P, ALP and PTH levels, whereas alopecia persists. The patient is still under treatment. The younger patient was introduced to treatment at the time of admission to our hospital (6 years of age) and her therapeutic regimen is still under adjustment, as there was no adequate response to 0.6 μg/kg/day of 1α-calcidiol. It is worth noting that there is a remarkable improvement in the patient’s clinical phenotype, as she is now able to walk and run without any pain despite the severe deformities. Our previous experience, from 4 other HVDRR patients treated in our department, has shown that the first signs of biochemical improvement appear 1.5–4 years after the introduction to the therapeutic regimen with oral calcium and 1α-calcidiol [30]. According to the literature, the patient’s response to treatment depends on the presence or absence of alopecia and the site of the VDR mutation, which designate the severity of the syndrome [31]. In brief, 2 patients with the nonsense mutation p.R73X were treated with 1 μg/kg/day of 1α-calcidiol and 1 g of oral calcium since the ages of 22 and 2 months, respec-

tively. Serum markers and skeletal growth improvement were obvious after 18 months and 3 years of treatment, respectively. The other 2 patients, who carried the p.Q92fs mutation, were treated with 1 g of oral calcium and 1.5 μg/kg/day of 1α-calcidiol, which was gradually increased to 3 μg/kg/day. As no improvement was recorded, 1α-calcidiol was replaced by calcitriol at 1 μg/kg/day. The patients were introduced to treatment at the ages of 9 and 6 months, respectively, whereas signs of improvement in their health were noticed about 4 years later. Alopecia still persists in all these patients. In conclusion, the present report describes 2 new HVDRR patients with a novel nonsense mutation in the VDR gene. Both patients presented with severe bone deformities and total alopecia. Resistance to the therapeutic regimen was overcome with high doses of 1α-calcidiol for a long period of time in the older patient, whereas treatment for the younger patient is still under adjustment.

Two HVDRR Patients with a Novel Nonsense Mutation in the VDR Gene

Horm Res Paediatr 2014;82:206–212 DOI: 10.1159/000362618

Acknowledgments The authors are indebted to the patients and their families for collaboration with this study.

Disclosure Statement

References

1 Malloy PJ, Pike JW, Feldman D: The vitamin D receptor and the syndrome of hereditary 1,25-dihydroxyvitamin D-resistant rickets. Endocr Rev 1999;20:156–188. 2 Haussler MR, Jurutka PW, Mizwicki M, Norman AW: Vitamin D receptor (VDR)-mediated actions of 1α,25(OH)2vitamin D3: genomic and non-genomic mechanisms. Best Pract Res Clin Endocrinol Metab 2011; 25: 543–559. 3 Rosen CJ, Adams JS, Bikle DD, Black DM, Demay MB, Manson JE, Murad MH, Kovacs CS: The nonskeletal effects of vitamin D: an Endocrine Society scientific statement. Endocr Rev 2012;33:456–492. 4 Malloy PJ, Feldman D: Genetic disorders and defects in vitamin d action. Endocrinol Metab Clin North Am 2010; 39: 333–346, table of contents. 5 St-Arnaud R: The direct role of vitamin D on bone homeostasis. Arch Biochem Biophys 2008;473:225–230. 6 Malloy PJ, Feldman D: The role of vitamin D receptor mutations in the development of alopecia. Mol Cell Endocrinol 2011;347:90–96.

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The authors declare that they have no conflict of interest.

212

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20

21

22

23

24

25

26

27

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mutations confer reduced transactivation in response to ligand and impaired interaction with the retinoid X receptor heterodimeric partner. Mol Endocrinol 1996;10:1617–1631. Malloy PJ, Eccleshall TR, Gross C, Van Maldergem L, Bouillon R, Feldman D: Hereditary vitamin D-resistant rickets caused by a novel mutation in the vitamin D receptor that results in decreased affinity for hormone and cellular hyporesponsiveness. J Clin Invest 1997;99:297–304. Nguyen TM, Adiceam P, Kottler ML, Guillozo H, Rizk-Rabin M, Brouillard F, Lagier P, Palix C, Garnier JM, Garabedian M: Tryptophan missense mutation in the ligand-binding domain of the vitamin D receptor causes severe resistance to 1,25-dihydroxyvitamin D. J Bone Miner Res 2002;17:1728–1737. Nguyen M, d’Alesio A, Pascussi JM, Kumar R, Griffin MD, Dong X, Guillozo H, Rizk-Rabin M, Sinding C, Bougneres P, Jehan F, Garabedian M: Vitamin D-resistant rickets and type 1 diabetes in a child with compound heterozygous mutations of the vitamin D receptor (L263R and R391S): dissociated responses of the CYP-24 and rel-B promoters to 1,25-dihydroxyvitamin D3. J Bone Miner Res 2006;21: 886–894. Cockerill FJ, Hawa NS, Yousaf N, Hewison M, O’Riordan JL, Farrow SM: Mutations in the vitamin D receptor gene in three kindreds associated with hereditary vitamin D-resistant rickets. J Clin Endocrinol Metab 1997; 82: 3156–3160. Malloy PJ, Zhu W, Zhao XY, Pehling GB, Feldman D: A novel inborn error in the ligand-binding domain of the vitamin D receptor causes hereditary vitamin D-resistant rickets. Mol Genet Metab 2001;73:138–148. Miller J, Djabali K, Chen T, Liu Y, Ioffreda M, Lyle S, Christiano AM, Holick M, Cotsarelis G: Atrichia caused by mutations in the vitamin D receptor gene is a phenocopy of generalized atrichia caused by mutations in the hairless gene. J Invest Dermatol 2001; 117: 612–617. Arita K, Nanda A, Wessagowit V, Akiyama M, Alsaleh QA, McGrath JA: A novel mutation in the VDR gene in hereditary vitamin D-resistant rickets. Br J Dermatol 2008; 158: 168–171. Kristjansson K, Rut AR, Hewison M, O’Riordan JL, Hughes MR: Two mutations in the hormone binding domain of the vitamin D receptor cause tissue resistance to 1,25-dihydroxyvitamin D3. J Clin Invest 1993; 92: 12–16. Malloy PJ, Wang J, Peng L, Nayak S, Sisk JM, Thompson CC, Feldman D: A unique insertion/duplication in the VDR gene that truncates the VDR causing hereditary 1,25-dihydroxyvitamin D-resistant rickets without alopecia. Arch Biochem Biophys 2007;460: 285–292. Malloy PJ, Xu R, Peng L, Clark PA, Feldman D: A novel mutation in helix 12 of the vitamin D receptor impairs coactivator interaction

Horm Res Paediatr 2014;82:206–212 DOI: 10.1159/000362618

29

30

31 32

33

34

35

36

37

38

39

40

and causes hereditary 1,25-dihydroxyvitamin D-resistant rickets without alopecia. Mol Endocrinol 2002;16:2538–2546. Wang J, Malloy PJ, Feldman D: Interactions of the vitamin D receptor with the corepressor hairless: analysis of hairless mutants in atrichia with papular lesions. J Biol Chem 2007;282: 25231–25239. Nicolaidou P, Tsitsika A, Papadimitriou A, Karantana A, Papadopoulou A, Psychou F, Liakopoulou D, Georgouli H, Kakourou T, Chrousos G: Hereditary vitamin D-resistant rickets in Greek children: genotype, phenotype, and long-term response to treatment. J Pediatr Endocrinol Metab 2007;20:425–430. Malloy PJ, Feldman D: Vitamin D resistance. Am J Med 1999;106:355–370. Hawa NS, Cockerill FJ, Vadher S, Hewison M, Rut AR, Pike JW, O’Riordan JLH, Farrow SM: Identification of a novel mutation in hereditary vitamin D resistant rickets causing exon skipping. Clin Endocrinol 1996;45:85–92. Malloy P, Xu R, Cattani A, Reyes ML, Feldman D: A unique insertion/substitution in helix H1 of the vitamin receptor ligand binding domain in a patient with hereditary 1,25-dihydroxyvitamin D-resistant rickets. J Bone Miner Res 2004;19:1018–1024. Thompson E, Kristjansson K, Hughes M: Molecular scanning methods for mutation detection: application to the 1,25-dihydroxyvitamin D receptor. Eighth Workshop on Vitamin D, Paris, France, 1991. Malloy P, Xu R, Peng L, Peleg S, Al-Ashwal A, Feldman D: Hereditary 1,25-dihydroxyvitamin D resistant rickets due to a mutation causing multiple defects in vitamin D receptor function. Endocrinology 2004; 145:5106– 5114. Aljubeh JM, Wang J, Al-Remeithi SS, Malloy PJ, Feldman D: Report of two unrelated patients with hereditary vitamin D resistant rickets due to the same novel mutation in the vitamin D receptor. J Pediatr Endocrinol Metab 2011;24:793–799. Ritchie H, Hughes M, Thompson E, Malloy P, Hochberg Z, Feldman D, Pike JW, O’Malley BW: An ochre mutation in the vitamin D receptor gene causes hereditary 1,25-dihydroxyvitamin D3-resistant rickets in three families. Proc Natl Acad Sci USA 1989; 86:9783–9787. Malloy P, Hochberg Z, Tiosano D, Pike JW, Hughes MR, Feldman D: The molecular basis of hereditary 1,25-dihydroxyvitamin D3 resistant rickets in seven related families. J Clin Invest 1990;86:2071–2079. Malloy P, Zhu W, Bouillon R, Feldman D: A novel nonsense mutation in the ligand binding domain of vitamin D receptor causes hereditary 1,25-dihydroxyvitamin D-resistant rickets. Mol Genet Metab 2002;77:314–318. Malloy P, Zhou Y, Wang J, Hiort O, Feldman D: Hereditary vitamin D-resistant rickets (HVDRR) owing to a heterozygous mutation in the vitamin D receptor. J Bone Miner Res 2011;26:2710–2718.

Papadopoulou et al.

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7 Kanakamani J, Tomar N, Kaushal E, Tandon N, Goswami R: Presence of a deletion mutation (c.716delA) in the ligand-binding domain of the vitamin D receptor in an Indian patient with vitamin D-dependent rickets type II. Calcif Tissue Int 2010;86:33–41. 8 Malloy PJ, Wang J, Srivastava T, Feldman D: Hereditary 1,25-dihydroxyvitamin D-resistant rickets with alopecia resulting from a novel missense mutation in the DNA-binding domain of the vitamin D receptor. Mol Genet Metab 2010;99:72–79. 9 Supornsilchai V, Hiranras Y, Wacharasindhu S, Mahayosnond A, Suphapeetiporn K, Shotelersuk V: Two siblings with a novel nonsense mutation, p.R50X, in the vitamin D receptor gene. Endocrine 2011;40:62–66. 10 Asunis I, Marini MG, Porcu L, Meloni A, Cabriolu AL, Cao A, Moi P: A novel missense mutation (C84R) in a patient with type II vitamin D-dependent rickets. Exp Clin Endocrinol Diabetes 2010;118:177–179. 11 Song JK, Yoon KS, Shim KS, Bae CW: Novel compound heterozygous mutations in the vitamin D receptor gene in a Korean girl with hereditary vitamin D-resistant rickets. J Korean Med Sci 2011;26:1111–1114. 12 Huang K, Malloy P, Feldman D, Pitukcheewanont P: Enteral calcium infusion used successfully as treatment for a patient with hereditary vitamin D resistant rickets (HVDRR) without alopecia: a novel mutation. Gene 2013;512:554–559. 13 Macedo LC, Soardi FC, Ananias N, Belangero VM, Rigatto SZ, De-Mello MP, D’Souza-Li L: Mutations in the vitamin D receptor gene in four patients with hereditary 1,25-dihydroxyvitamin D-resistant rickets. Arq Bras Endocrinol Metabol 2008;52:1244–1251. 14 Ma NS, Malloy PJ, Pitukcheewanont P, Dreimane D, Geffner ME, Feldman D: Hereditary vitamin D resistant rickets: identification of a novel splice site mutation in the vitamin D receptor gene and successful treatment with oral calcium therapy. Bone 2009;45:743–746. 15 Zhou Y, Wang J, Malloy PJ, Dolezel Z, Feldman D: Compound heterozygous mutations in the vitamin D receptor in a patient with hereditary 1,25-dihydroxyvitamin D-resistant rickets with alopecia. J Bone Miner Res 2009;24:643–651. 16 Malloy PJ, Weisman Y, Feldman D: Hereditary 1α,25-dihydroxyvitamin D-resistant rickets resulting from a mutation in the vitamin D receptor deoxyribonucleic acid-binding domain. J Clin Endocrinol Metab 1994;78:313–316. 17 Nicolaidou P, Papadopoulou A, Matsinos YG, Georgouli H, Fretzayas A, Papadimitriou A, Prifitis K, Douros K, Chrousos GP: Vitamin D receptor polymorphisms in hypocalcemic vitamin D-resistant rickets carriers. Horm Res 2007:67:179–183. 18 Whitfield GK, Selznick SH, Haussler CA, Hsieh JC, Galligan MA, Jurutka PW, Thompson PD, Lee SM, Zerwekh JE, Haussler MR: Vitamin D receptors from patients with resistance to 1,25-dihydroxyvitamin D3: point

Identification of a novel nonsense mutation in the ligand-binding domain of the vitamin d receptor gene and clinical description of two greek patients with hereditary vitamin d-resistant rickets and alopecia.

We analyzed the vitamin D receptor (VDR) gene in 2 Greek patients who exhibited the classical features of hereditary vitamin D-resistant rickets (HVDR...
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