EDITORIAL URRENT C OPINION
Editorial comments: endocrinology and metabolism 2015 Allen W. Root
In the August 2015 endocrine and metabolism section of Current Opinion in Pediatrics, Drs. Tilg and Adolph (pp. 496–501) introduce the concept of the human microbiome and review the effect of the human intestinal microbiome on body weight, carbohydrate metabolism, and immune function; Drs. Liu, Garrison, and Baron (pp. 502–510) consider the multiple environmental, hormonal, and genetic factors that regulate body growth; Drs. Gordon, Kanaoka, and Nelson (pp. 511–519) discuss the genetic mutations, autoimmune disorders, and environmental and medically related insults that impair ovarian differentiation and function, and oogenesis; Drs. Hutson and Thorup (pp. 520–524) review the mechanisms that regulate the descent of the testis from its site of differentiation in the fetal mesenchyme to the scrotum, and the current best practice for the management of an infant male with cryptorchidism, and Drs. Hameed, Jaffe, and Verge (pp. 525–533) discuss the adverse effects of cystic fibrosis on carbohydrate metabolism and the clinical consequences thereof. The microbiome (or microbiota) is the term applied to the bacterial, fungal, viral, and parasitic populations that usually reside in harmony with the healthy living host. These organisms are to be found on multiple skin sites and crevasses (e.g., retroauricular crease, external auditory canal, antecubital and popliteal fossae, umbilicus, and finger and toe interdigital spaces), anterior nares, oral cavity (buccal mucosa, hard palate, tonsils, and dorsum of tongue), vagina, and lower intestinal tract. Collectively, the mass of these microorganisms weighs 0.21.5 kg in the average human adult. Because the majority of organisms constituting the microbiome cannot be cultured, they have been identified by sequencing their DNA or RNA in samples obtained from selected body sites combined with computational analytic techniques enabling the separate identification of individual microorganisms. These microorganisms have diverse effects on body homeostasis; in the intestinal tract, the resident microbes influence the digestion of foodstuffs, nutrient absorption, and energy availability. As discussed by Tilg and Adolph, alteration in the www.co-pediatrics.com
body’s intestinal microbial composition induced by diet or antibiotic usage may impact the processes of energy conservation and weight gain, systemic metabolism, and immune homeostasis. Alteration of the microbiome has been associated with disorders such as obesity, type 2 diabetes mellitus, inflammatory bowel disease, and rheumatoid arthritis. Terms commonly used when alluding to the microbiome, that may cause some confusion, are probiotic and prebiotic. A probiotic is a microorganism(s) that when specifically ingested may be of benefit to the recipient host. A prebiotic is a dietary foodstuff most often a fibrous material that is unable to be digested by the host but one that can be utilized by intestinal organisms as an energy source; some skin products may also serve as prebiotics. The sizes of the mammalian body and its internal organs are regulated by multiple exogenous and endogenous factors as described by Drs. Liu, Garrison, and Baron. In addition to reviewing the known effects of nutrition and pituitary, thyroid, and gonadal sex hormones upon growth, the authors introduce the readers to a molecular pathway through which body and organ size may be regulated the HIPPO pathway a series of reactions that ultimately inhibits cell proliferation and growth as illustrated in the authors’ first figure. These investigators also discuss a gene (E2F3) that may be a prominent guide to the deceleration in body and organ growth that occurs as adult stature is achieved. They review the current data concerning the genome wide association studies that have identified more than 400 genes related to adult height, including 78 genes essential for proliferation and function of the chondrocytes of the cartilaginous growth plates, and discuss epigenetic All Children’s Hospital/Johns Hopkins Medicine, St. Petersburg, Florida, USA Correspondence to Allen W. Root, MD, Division of Endocrinology and Diabetes, All Children’s Hospital/Johns Hopkins Medicine, 501 Sixth Avenue South, St. Petersburg, FL 33701, USA. E-mail: [email protected] Curr Opin Pediatr 2015, 27:492–495 DOI:10.1097/MOP.0000000000000248 Volume 27 Number 4 August 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Editorial comments: endocrinology and metabolism 2015 Root
variations that may be responsible for syndromes of excessive growth. The most common form of ovarian malformation encountered in children and adolescents is the Turner syndrome of gonadal dysgenesis, associated with the absence of one X chromosome in all cells (karyotype: 45X) or most cells (karyotype: mosaic 45X/46XX) or abnormality of formation of one of the two X chromosomes (karyotype: 45XXqi ¼ isochromosome of the long arm of the second X chromosome). Drs. Gordon, Kanaoka, and Nelson discuss other causes of primary ovarian insufficiency less commonly encountered. Although rare in terms of number of affected patients identified to date, gene mutations that result in primary ovarian insufficiency demonstrate the complexity of ovarian differentiation and oocyte development and the many factors essential for the maturation of the oocyte and ovulation. Table 1 lists the presently identified genes required for this process, mutations of which have resulted in ovarian dysgenesis or primary ovarian failure (or both) as designated and classified in the Online Mendelian Inheritance in Man database. In this classification, mutations in FSHR and BMP15 have been associated with both ovarian dysgenesis and premature ovarian failure. (As Gordon et al. point out, the term premature ovarian insufficiency includes disorders related to hypergonadotropic hypogonadism, ovarian dysgenesis, and ovarian failure.) Drs. Hutson and Thorup discuss the mechanical and hormonal factors that guide the descent of the embryonic testis from its retroperitoneal origin in the urogenital ridge to the scrotum. They emphasize the need for surgical movement of the cryptorchid testis to the scrotum between 6 and 12 months of age in order to preserve spermatogenesis to the maximum extent possible. Drs. Hameed, Jaffe, and Verge explore the effect of cystic fibrosis upon pancreatic islet b-cell function and insulin secretion. Not only is glucose intolerance common in children with cystic fibrosis, hyperglycemia and insulin deficiency themselves adversely affect the clinical course of the primary disease. They do so by promoting an environment that enhances respiratory tract overgrowth of harmful pathogens and by impairing growth, weight gain, and effective lung and airway function. Syndromes of premature aging include the HutchinsonGilford Progeria Syndrome (HGPS), due to loss of function mutations in LMNA, and the syndromes of Werner, Bloom, RothmundThompson, and Cockayne, due to mutations in RECQL2, RECQL3, RECQL4, and ERCC8, respectively. HGPS is clinically characterized by the early infancy onset of premature aging with severe
arteriosclerotic heart and cerebrovascular disease leading to early demise; other features include short stature, hair loss, scleroderma, lipodystrophy, and primary gonadal failure. Intelligence is normal in patients with HGPS. (There is also a form of HGPS that begins in late childhood.) HGPS is due to de-novo heterozygous deletions or mutations in LMNA encoding lamins A and C two proteins derived from a common preprotein by alternative splicing that are constituents of the nuclear membrane. The nuclear membrane is composed of outer and inner membranes interior to which is the nuclear lamina, which forms a protein network underlying and interior to the inner nuclear membrane. Loss of the nuclear lamina results in nuclear distortion for example, lobulation, thickening of the nuclear membrane, loss of heterochromatin, clustering of nuclear pores rendering the nucleus sensitive to mechanical stress, and the cell subject to premature aging and apoptosis. The HGPS mutations in LMNA prevent removal of a farnesyl group that is added to prelamin A as a posttranslational modification and is later removed during further maturation of the protein. Prelamin A is converted into lamin A by removal of 18 carboxyl terminal amino acids. This is accomplished by isoprenylation and farnesylation of a specific sequence of C-terminal amino acids (aa) cysteine-aliphatic aa-aliphatic aa-any aa (CaaX). Farnesyl is an isoprenoid with a 15-carbon hydrophobic sequence of amino acids. Farnesyltransferase catalyzes the placement of farnesyl on the carboxyl terminal CaaX motif of the target protein. Prelamin A is first farnesylated, then carboxymethylated, and then proteolytically cleaved after Tyr646 by Zmpste24, a metalloproteinase, to produce mature lamin A. Mutations (deletions and amino acid variants) in LMNA result in an inability to remove the carboxyl-terminal farnesyl group which renders the altered protein (termed progerin) ‘toxic’ to the nuclear membrane. Interestingly, synthetic-mutated Lamin A protein that is not farnesylated does not adversely affect cell longevity. Farnesylation may be inhibited in vitro by statins that impair HMG CoA reductase, that reduces mevalonate production an intermediate in the synthesis of farnesyl; bisphosphonates that interfere with conversion of mevalonate into farnesyl; and inhibitors of farnesyltransferase one such inhibitor is lonafarnib a synthetic tricyclic derivative of carboxamide. Gordon et al. [1] demonstrated that administration of lonafarnib for 2 years to 25 patients with HGPS resulted in substantial weight gain, decreased arterial pulse wave velocity and carotid artery echodensity, and increase in skeletal rigidity and
1040-8703 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-pediatrics.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
493
494
www.co-pediatrics.com
MCM9 (MCMDC1) 6q22.31 Minichromosome maintenance complex component 9 610098
FMR1 Xq27.3 Fragile X mental retardation protein 309550
DIAPH2 Xq21.33 Diaphanous, Drosophila A, homolog of 300108
POF1B Xq21.1-q21.2 Actin binding protein, 34-kd 30603
FOXL2 3q22.3 Forkhead transcription factor FOXL2 605597
BMP15 Xp11.22 Bone morphogenetic protein 15 300247
NOBOX 7q35 Newborn ovary homeobox, mouse, homolog of 610934
FIGLA 2p13.3 Factor in germline alpha, mouse, homolog of 608697
NR5A1 9q33.3 Nuclear receptor subfamily 5, group A, member 1 184757
STAG3 7q22.11 Stromalin 3 608489
HFM1 1p22.2 HFM1, ATP-dependent DNA helicase, Saccharomyces cerevisiae, homolog of 615684 MCM8 20p12.3 Minichromosome maintenance complex component 8 608187
ODG 4 616185
POF 1 311360
POF 2A 300511
POF 2B 300604
POF 3 608996
POF 4 300510
POF 5 611548
POF 6 612310
POF 7 612964
POF 8 615213
POF 9 615724
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
ZP1 11q12.2 Zona pellucida glycoprotein 1 195000
Oocyte maturation defect
One of four glycoproteins expressed in the zona pellucida; essential for oocyte maturation and fertilization; LOF AR
Essential for completion of meiosis; LOF AR
Essential for initiation of DNA replication; interacts with MCM9; LOF AR
Helicase separates DNA strands using energy from ATP; LOF variants result in blockage of oogenesis and spermatogenesis AR
Encodes subunit of cohesin essential for pairing and segregation of chromosomes during meiosis; LOF AR
(Steroidogenic factor 1) Transcription factor regulates transcription of MIS and SRY, gonadal differentiation and steroidogenesis; LOF variants associated with XY sex reversal, adrenocortical insufficiency, spermatogenic failure and POF; monoallelic
Transcription factor expressed in all phases of folliculogenesis; LOF monoallelic
Essential for expression of oocyte-specific genes and folliculogenesis; LOF monoallelic
Expressed in oocytes of late primary follicles; selectively modulates FSH function; LOF mutations associated with ODG and POF; monoallelic X-linked
Interacts with NR5A1 to influence transcription of multiple genes; LOF monoallelic
Binds actin; directs pairing of meiotic chromosomes; escapes X inactivation; LOF monoallelic X-linked
Interacts with actin; essential for metaphase chromosome alignment; LOF mutations result in mitotic errors; monoallelic X-linked
Complexes with ribosomes and messenger RNA to regulate protein translation; 200 CGG repeats; LOF monoallelic X-linked
Adapted from Online Mendelian Inheritance in Man. AR, autosomal recessive; LOF, loss of function; ODG, ovarian dysgenesis; POF, premature ovarian failure. a PSMC3 proteasome 26S subunit, ATPase 3.
SYCE1 10q26.3 Synaptonemal complex central element protein 1 611486
POF
POF 10 612885
Coactivator of the nuclear estrogen receptor; necessary for estrogen-mediated gene transcription; LOF AR
PSMC31P 17q21.1 PSMC3a interacting protein 608665
ODG 3 614324 Essential for initiation of DNA repair and replication; interacts with MCM8; LOF AR
Expressed in oocytes of late primary follicles; selectively modulates FSH function; LOF associated with ODG and POF; monoallelic X-linked
BMP15 Xp11.22 Bone morphogenetic protein 15 300247
ODG 2 300510
Seven transmembrane G-protein coupled receptor initiates intracellular signal transduction; LOF associated with ODG and POF; AR
Function
FSHR 2p16.3 Follicle stimulating hormone receptor 136435
Gene/locus/OMIM
ODG 1 233300
Type/OMIM
Table 1. Ovarian dysgenesis/premature ovarian failure: gene mutations
Endocrinology and metabolism
Volume 27 Number 4 August 2015
Editorial comments: endocrinology and metabolism 2015 Root
sensorineural hearing with decline in the frequency of headaches, seizures, and cerebrovascular accidents. These findings were later extended to include groups of HGPS patients receiving monotherapy with lonafarnib for 2 years and then combined the treatment with lonafarnib, zoledronate, and pravastatin therapy for 3.5 years. Overall, 43 HGPS patients were treated for 5þ years at which point mortality was assessed and compared with matched untreated HGPS patients. In matched untreated HGPS patients, median survival was 14.5 years mean survival was 14.6 years and was sex independent. Survival in 43 untreated patients after 5 years was 51.1%, whereas in 43 treated patients survival after 5 years was 88.4%. Extension in mean survival after 6 years of treatment was 1.6 years [confidence interval (CI) 0.8–2.4 years]. The authors concluded that inhibition of farnesylation increased survival of HGPS patients. Oshima et al. [2] discussed the role of progerin (small amounts of which can be
detected in normal individuals) in human aging and cardiovascular disease and postulated the use of anti-lamin A agents to extend life. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES 1.
2.
Gordon LB, Massaro J, D’Agostino RB, et al. Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome. Circulation 2014; 130:27–34. Oshima J, Hisama FM, Martin GM. An encouraging progress report on the treatment of progeria and its implications for atherogenesis. Circulation 2014; 130:4–6.
1040-8703 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-pediatrics.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
495
Editorial comments: endocrinology and metabolism 2015 Allen W. Root
In the August 2015 endocrine and metabolism section of Current Opinion in Pediatrics, Drs. Tilg and Adolph (pp. 496–501) introduce the concept of the human microbiome and review the effect of the human intestinal microbiome on body weight, carbohydrate metabolism, and immune function; Drs. Liu, Garrison, and Baron (pp. 502–510) consider the multiple environmental, hormonal, and genetic factors that regulate body growth; Drs. Gordon, Kanaoka, and Nelson (pp. 511–519) discuss the genetic mutations, autoimmune disorders, and environmental and medically related insults that impair ovarian differentiation and function, and oogenesis; Drs. Hutson and Thorup (pp. 520–524) review the mechanisms that regulate the descent of the testis from its site of differentiation in the fetal mesenchyme to the scrotum, and the current best practice for the management of an infant male with cryptorchidism, and Drs. Hameed, Jaffe, and Verge (pp. 525–533) discuss the adverse effects of cystic fibrosis on carbohydrate metabolism and the clinical consequences thereof. The microbiome (or microbiota) is the term applied to the bacterial, fungal, viral, and parasitic populations that usually reside in harmony with the healthy living host. These organisms are to be found on multiple skin sites and crevasses (e.g., retroauricular crease, external auditory canal, antecubital and popliteal fossae, umbilicus, and finger and toe interdigital spaces), anterior nares, oral cavity (buccal mucosa, hard palate, tonsils, and dorsum of tongue), vagina, and lower intestinal tract. Collectively, the mass of these microorganisms weighs 0.21.5 kg in the average human adult. Because the majority of organisms constituting the microbiome cannot be cultured, they have been identified by sequencing their DNA or RNA in samples obtained from selected body sites combined with computational analytic techniques enabling the separate identification of individual microorganisms. These microorganisms have diverse effects on body homeostasis; in the intestinal tract, the resident microbes influence the digestion of foodstuffs, nutrient absorption, and energy availability. As discussed by Tilg and Adolph, alteration in the www.co-pediatrics.com
body’s intestinal microbial composition induced by diet or antibiotic usage may impact the processes of energy conservation and weight gain, systemic metabolism, and immune homeostasis. Alteration of the microbiome has been associated with disorders such as obesity, type 2 diabetes mellitus, inflammatory bowel disease, and rheumatoid arthritis. Terms commonly used when alluding to the microbiome, that may cause some confusion, are probiotic and prebiotic. A probiotic is a microorganism(s) that when specifically ingested may be of benefit to the recipient host. A prebiotic is a dietary foodstuff most often a fibrous material that is unable to be digested by the host but one that can be utilized by intestinal organisms as an energy source; some skin products may also serve as prebiotics. The sizes of the mammalian body and its internal organs are regulated by multiple exogenous and endogenous factors as described by Drs. Liu, Garrison, and Baron. In addition to reviewing the known effects of nutrition and pituitary, thyroid, and gonadal sex hormones upon growth, the authors introduce the readers to a molecular pathway through which body and organ size may be regulated the HIPPO pathway a series of reactions that ultimately inhibits cell proliferation and growth as illustrated in the authors’ first figure. These investigators also discuss a gene (E2F3) that may be a prominent guide to the deceleration in body and organ growth that occurs as adult stature is achieved. They review the current data concerning the genome wide association studies that have identified more than 400 genes related to adult height, including 78 genes essential for proliferation and function of the chondrocytes of the cartilaginous growth plates, and discuss epigenetic All Children’s Hospital/Johns Hopkins Medicine, St. Petersburg, Florida, USA Correspondence to Allen W. Root, MD, Division of Endocrinology and Diabetes, All Children’s Hospital/Johns Hopkins Medicine, 501 Sixth Avenue South, St. Petersburg, FL 33701, USA. E-mail: [email protected] Curr Opin Pediatr 2015, 27:492–495 DOI:10.1097/MOP.0000000000000248 Volume 27 Number 4 August 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Editorial comments: endocrinology and metabolism 2015 Root
variations that may be responsible for syndromes of excessive growth. The most common form of ovarian malformation encountered in children and adolescents is the Turner syndrome of gonadal dysgenesis, associated with the absence of one X chromosome in all cells (karyotype: 45X) or most cells (karyotype: mosaic 45X/46XX) or abnormality of formation of one of the two X chromosomes (karyotype: 45XXqi ¼ isochromosome of the long arm of the second X chromosome). Drs. Gordon, Kanaoka, and Nelson discuss other causes of primary ovarian insufficiency less commonly encountered. Although rare in terms of number of affected patients identified to date, gene mutations that result in primary ovarian insufficiency demonstrate the complexity of ovarian differentiation and oocyte development and the many factors essential for the maturation of the oocyte and ovulation. Table 1 lists the presently identified genes required for this process, mutations of which have resulted in ovarian dysgenesis or primary ovarian failure (or both) as designated and classified in the Online Mendelian Inheritance in Man database. In this classification, mutations in FSHR and BMP15 have been associated with both ovarian dysgenesis and premature ovarian failure. (As Gordon et al. point out, the term premature ovarian insufficiency includes disorders related to hypergonadotropic hypogonadism, ovarian dysgenesis, and ovarian failure.) Drs. Hutson and Thorup discuss the mechanical and hormonal factors that guide the descent of the embryonic testis from its retroperitoneal origin in the urogenital ridge to the scrotum. They emphasize the need for surgical movement of the cryptorchid testis to the scrotum between 6 and 12 months of age in order to preserve spermatogenesis to the maximum extent possible. Drs. Hameed, Jaffe, and Verge explore the effect of cystic fibrosis upon pancreatic islet b-cell function and insulin secretion. Not only is glucose intolerance common in children with cystic fibrosis, hyperglycemia and insulin deficiency themselves adversely affect the clinical course of the primary disease. They do so by promoting an environment that enhances respiratory tract overgrowth of harmful pathogens and by impairing growth, weight gain, and effective lung and airway function. Syndromes of premature aging include the HutchinsonGilford Progeria Syndrome (HGPS), due to loss of function mutations in LMNA, and the syndromes of Werner, Bloom, RothmundThompson, and Cockayne, due to mutations in RECQL2, RECQL3, RECQL4, and ERCC8, respectively. HGPS is clinically characterized by the early infancy onset of premature aging with severe
arteriosclerotic heart and cerebrovascular disease leading to early demise; other features include short stature, hair loss, scleroderma, lipodystrophy, and primary gonadal failure. Intelligence is normal in patients with HGPS. (There is also a form of HGPS that begins in late childhood.) HGPS is due to de-novo heterozygous deletions or mutations in LMNA encoding lamins A and C two proteins derived from a common preprotein by alternative splicing that are constituents of the nuclear membrane. The nuclear membrane is composed of outer and inner membranes interior to which is the nuclear lamina, which forms a protein network underlying and interior to the inner nuclear membrane. Loss of the nuclear lamina results in nuclear distortion for example, lobulation, thickening of the nuclear membrane, loss of heterochromatin, clustering of nuclear pores rendering the nucleus sensitive to mechanical stress, and the cell subject to premature aging and apoptosis. The HGPS mutations in LMNA prevent removal of a farnesyl group that is added to prelamin A as a posttranslational modification and is later removed during further maturation of the protein. Prelamin A is converted into lamin A by removal of 18 carboxyl terminal amino acids. This is accomplished by isoprenylation and farnesylation of a specific sequence of C-terminal amino acids (aa) cysteine-aliphatic aa-aliphatic aa-any aa (CaaX). Farnesyl is an isoprenoid with a 15-carbon hydrophobic sequence of amino acids. Farnesyltransferase catalyzes the placement of farnesyl on the carboxyl terminal CaaX motif of the target protein. Prelamin A is first farnesylated, then carboxymethylated, and then proteolytically cleaved after Tyr646 by Zmpste24, a metalloproteinase, to produce mature lamin A. Mutations (deletions and amino acid variants) in LMNA result in an inability to remove the carboxyl-terminal farnesyl group which renders the altered protein (termed progerin) ‘toxic’ to the nuclear membrane. Interestingly, synthetic-mutated Lamin A protein that is not farnesylated does not adversely affect cell longevity. Farnesylation may be inhibited in vitro by statins that impair HMG CoA reductase, that reduces mevalonate production an intermediate in the synthesis of farnesyl; bisphosphonates that interfere with conversion of mevalonate into farnesyl; and inhibitors of farnesyltransferase one such inhibitor is lonafarnib a synthetic tricyclic derivative of carboxamide. Gordon et al. [1] demonstrated that administration of lonafarnib for 2 years to 25 patients with HGPS resulted in substantial weight gain, decreased arterial pulse wave velocity and carotid artery echodensity, and increase in skeletal rigidity and
1040-8703 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-pediatrics.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
493
494
www.co-pediatrics.com
MCM9 (MCMDC1) 6q22.31 Minichromosome maintenance complex component 9 610098
FMR1 Xq27.3 Fragile X mental retardation protein 309550
DIAPH2 Xq21.33 Diaphanous, Drosophila A, homolog of 300108
POF1B Xq21.1-q21.2 Actin binding protein, 34-kd 30603
FOXL2 3q22.3 Forkhead transcription factor FOXL2 605597
BMP15 Xp11.22 Bone morphogenetic protein 15 300247
NOBOX 7q35 Newborn ovary homeobox, mouse, homolog of 610934
FIGLA 2p13.3 Factor in germline alpha, mouse, homolog of 608697
NR5A1 9q33.3 Nuclear receptor subfamily 5, group A, member 1 184757
STAG3 7q22.11 Stromalin 3 608489
HFM1 1p22.2 HFM1, ATP-dependent DNA helicase, Saccharomyces cerevisiae, homolog of 615684 MCM8 20p12.3 Minichromosome maintenance complex component 8 608187
ODG 4 616185
POF 1 311360
POF 2A 300511
POF 2B 300604
POF 3 608996
POF 4 300510
POF 5 611548
POF 6 612310
POF 7 612964
POF 8 615213
POF 9 615724
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
ZP1 11q12.2 Zona pellucida glycoprotein 1 195000
Oocyte maturation defect
One of four glycoproteins expressed in the zona pellucida; essential for oocyte maturation and fertilization; LOF AR
Essential for completion of meiosis; LOF AR
Essential for initiation of DNA replication; interacts with MCM9; LOF AR
Helicase separates DNA strands using energy from ATP; LOF variants result in blockage of oogenesis and spermatogenesis AR
Encodes subunit of cohesin essential for pairing and segregation of chromosomes during meiosis; LOF AR
(Steroidogenic factor 1) Transcription factor regulates transcription of MIS and SRY, gonadal differentiation and steroidogenesis; LOF variants associated with XY sex reversal, adrenocortical insufficiency, spermatogenic failure and POF; monoallelic
Transcription factor expressed in all phases of folliculogenesis; LOF monoallelic
Essential for expression of oocyte-specific genes and folliculogenesis; LOF monoallelic
Expressed in oocytes of late primary follicles; selectively modulates FSH function; LOF mutations associated with ODG and POF; monoallelic X-linked
Interacts with NR5A1 to influence transcription of multiple genes; LOF monoallelic
Binds actin; directs pairing of meiotic chromosomes; escapes X inactivation; LOF monoallelic X-linked
Interacts with actin; essential for metaphase chromosome alignment; LOF mutations result in mitotic errors; monoallelic X-linked
Complexes with ribosomes and messenger RNA to regulate protein translation; 200 CGG repeats; LOF monoallelic X-linked
Adapted from Online Mendelian Inheritance in Man. AR, autosomal recessive; LOF, loss of function; ODG, ovarian dysgenesis; POF, premature ovarian failure. a PSMC3 proteasome 26S subunit, ATPase 3.
SYCE1 10q26.3 Synaptonemal complex central element protein 1 611486
POF
POF 10 612885
Coactivator of the nuclear estrogen receptor; necessary for estrogen-mediated gene transcription; LOF AR
PSMC31P 17q21.1 PSMC3a interacting protein 608665
ODG 3 614324 Essential for initiation of DNA repair and replication; interacts with MCM8; LOF AR
Expressed in oocytes of late primary follicles; selectively modulates FSH function; LOF associated with ODG and POF; monoallelic X-linked
BMP15 Xp11.22 Bone morphogenetic protein 15 300247
ODG 2 300510
Seven transmembrane G-protein coupled receptor initiates intracellular signal transduction; LOF associated with ODG and POF; AR
Function
FSHR 2p16.3 Follicle stimulating hormone receptor 136435
Gene/locus/OMIM
ODG 1 233300
Type/OMIM
Table 1. Ovarian dysgenesis/premature ovarian failure: gene mutations
Endocrinology and metabolism
Volume 27 Number 4 August 2015
Editorial comments: endocrinology and metabolism 2015 Root
sensorineural hearing with decline in the frequency of headaches, seizures, and cerebrovascular accidents. These findings were later extended to include groups of HGPS patients receiving monotherapy with lonafarnib for 2 years and then combined the treatment with lonafarnib, zoledronate, and pravastatin therapy for 3.5 years. Overall, 43 HGPS patients were treated for 5þ years at which point mortality was assessed and compared with matched untreated HGPS patients. In matched untreated HGPS patients, median survival was 14.5 years mean survival was 14.6 years and was sex independent. Survival in 43 untreated patients after 5 years was 51.1%, whereas in 43 treated patients survival after 5 years was 88.4%. Extension in mean survival after 6 years of treatment was 1.6 years [confidence interval (CI) 0.8–2.4 years]. The authors concluded that inhibition of farnesylation increased survival of HGPS patients. Oshima et al. [2] discussed the role of progerin (small amounts of which can be
detected in normal individuals) in human aging and cardiovascular disease and postulated the use of anti-lamin A agents to extend life. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES 1.
2.
Gordon LB, Massaro J, D’Agostino RB, et al. Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome. Circulation 2014; 130:27–34. Oshima J, Hisama FM, Martin GM. An encouraging progress report on the treatment of progeria and its implications for atherogenesis. Circulation 2014; 130:4–6.
1040-8703 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-pediatrics.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
495
