Genetic and Epigenetic Characteristics of Autosomal Dominant Pseudohypoparathyroidism Type 1B: Case Reports and Literature Review

Abstract

Autosomal dominant pseudohypoparathyroidism 1B (AD-PHP1B) is a rare endocrine and imprinted disorder. The objective of this study is to clarify the imprinted regulation of the guanine nucleotide binding-protein α-stimulating activity polypeptide 1 (GNAS) cluster in the occurrence and development of AD-PHP1B based on animal and clinical patient studies. The methylation-specific multiples ligation-dependent probe amplification (MS-MLPA) was conducted to detect the copy number variation in syntaxin-16 (STX16) gene and methylation status of the GNAS differentially methylated regions (DMRs). Long-range PCR was used to confirm deletion at STX16 gene. In the first family, DNA analysis of the proband and proband’s mother revealed an isolated loss of methylation (LOM) at exon A/B and a 3.0 kb STX16 deletion. The patient’s healthy grandmother had the 3.0 kb STX16 deletion but no epigenetic abnormality. The patient’s healthy maternal aunt showed no genetic or epigenetic abnormality. In the second family, the analysis of long-range PCR revealed the 3.0 kb STX16 deletion for the proband but not her children. In this study, 3.0 kb STX16 deletion causes isolated LOM at exon A/B in two families, which is the most common genetic mutation of AD-PHP1B. The deletion involving NESP55 or AS or genomic rearrangements of GNAS can also result in AD-PHP1B, but it's rare. LOM at exon A/B DMR is prerequisite methylation defect of AD-PHP1B. STX16 and NESP55 directly control the imprinting at exon A/B, while AS controls the imprinting at exon A/B by regulating the transcriptional level of NESP55.

Key words

autosomal dominant pseudohypoparathyroidism 1B - GNAS cluster - syntaxin-16 - epigenetics

Publication History

Received: 15 October 2020

Accepted: 13 December 2020

Article published online:
29 January 2021

• References

• 1 Levine MA. An update on the clinical and molecular characteristics of pseudohypoparathyroidism. Curr Opin Endocrinol Diabetes Obes 2012; 19: 443-451
• 2 Moore T, Haig D. Genomic imprinting in mammalian development: A parental tug-of-war. Trends Genet 1991; 7: 45-49
• 3 Weinstein LS, Gejman PV, Friedman E. et al. Mutations of the Gs α-subunit gene in Albright hereditary osteodystrophy detected by denaturing gradient gel electrophoresis. Proc Natl Acad Sci USA 1990; 87: 8287-8290
• 4 Mantovani G, Bastepe M, Monk D. et al. Diagnosis and management of pseudohypoparathyroidism and related disorders: First international Consensus Statement. Nat Rev Endocrinol 2018; 14: 476-500
• 5 Mantovani G, Bondioni S, Linglart A. et al. Genetic analysis and evaluation of resistance to thyrotropin and growth hormone-releasing hormone in pseudohypoparathyroidism type Ib. J Clin Endocrinol Metab 2007; 92: 3738-3742
• 6 Rochtus A, Martin-Trujillo A, Izzi B. et al. Genome-wide DNA methylation analysis of pseudohypoparathyroidism patients with GNAS imprinting defects. Clin Epigenetics 2016; 8: 10
• 7 Molinaro A, Tiosano D, Takatani R. et al. TSH elevations as the first laboratory evidence for pseudohypoparathyroidism type Ib (PHP-Ib). J Bone Miner Res 2015; 30: 906-912
• 8 Perez-Nanclares G, Romanelli V, Mayo S. et al. Detection of hypomethylation syndrome among patients with epigenetic alterations at the GNAS locus. J Clin Endocrinol Metab 2012; 97: 1060-1067
• 9 De Nanclares GP, Fernández-Rebollo E, Santin I. et al. Epigenetic defects of GNAS in patients with pseudohypoparathyroidism and mild features of Albright’s hereditary osteodystrophy. J Clin Endocrinol Metab 2007; 92: 2370-2373
• 10 Jüppner H, Schipani E, Bastepe M. et al. The gene responsible for pseudohypoparathyroidism type Ib is paternally imprinted and maps in four unrelated kindreds to chromosome 20q13.3. Proc Natl Acad Sci USA 1998; 95: 11798-11803
• 11 Reyes M, Karaca A, Bastepe M. et al. A novel deletion involving GNAS exon 1 causes PHP1A and further refines the region required for normal methylation at exon A/B. Bone 2017; 103: 281-286
• 12 Turan S, Ignatius J, Moilanen JS. et al. De novo STX16 deletions: An infrequent cause of pseudohypoparathyroidism type Ib that should be excluded in sporadic cases. J Clin Endocrinol Metab 2012; 97: 2314-2319
• 13 Campbell R, Gosden CM, Bonthron DT. Parental origin of transcription from the human GNAS1 gene. J Med Genet 1994; 607-614
• 14 Yu S, Yu D, Lee E. et al. Variable and tissue-specific hormone resistance in heterotrimeric Gs protein -subunit (Gs ) knockout mice is due to tissue-specific imprinting of the Gs gene. Proc Natl Acad Sci 1998; 95: 8715-8720
• 15 Mantovani G, Ballare E, Giammona E. et al. The Gsα gene: Predominant maternal origin of transcription in human thyroid gland and gonads. J Clin Endocrinol Metab 2002; 87: 4736-4740
• 16 Liu J, Erlichman B, Weinstein LS. The stimulatory G protein a-subunit Gsa is imprinted in human thyroid glands: Implications for thyroid function in pseudohypoparathyroidism types 1A and 1B. J Clin Endocrinol Metab 2003; 88: 4336-4341
• 17 Turan S, Fernandez-Rebollo E, Aydin C. et al. Postnatal establishment of allelic Gsα silencing as a plausible explanation for delayed onset of parathyroid hormone resistance owing to heterozygous Gas disruption. J Bone Miner Res 2014; 29: 749-760
• 18 Izzi B, Van Geet C, Freson K. Recent Advances in GNAS Epigenetic Research of Pseudohypoparathyroidism. Curr Mol Med 2012; 12: 566-573
• 19 Maupetit-Méhouas S, Mariot V, Reynès C. et al. Quantification of the methylation at the GNAS locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib. J Med Genet 2011; 48: 55-63
• 20 Bastepe M, Lane AH, Jüppner H. Paternal Uniparental Isodisomy of Chromosome 20q — and the Resulting Changes in GNAS1 Methylation — as a Plausible Cause of Pseudohypoparathyroidism. Am J Hum Genet 2002; 68: 1283-1289
• 21 Bastepe M, Altug-Teber Ö, Agarwal C. et al. Paternal uniparental isodisomy of the entire chromosome 20 as a molecular cause of pseudohypoparathyroidism type Ib (PHP-Ib). Bone 2011; 48: 659-662
• 22 Takatani R, Minagawa M, Molinaro A. et al. Similar frequency of paternal uniparental disomy involving chromosome 20q (patUPD20q) in Japanese and Caucasian patients affected by sporadic pseudohypoparathyroidism type Ib (sporPHP1B). Bone 2015; 79: 15-20
• 23 Bastepe M, Fröhlich LF, Hendy GN. et al. Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS. J Clin Invest 2003; 112: 1255-1263
• 24 Linglart A, Gensure RC, Olney RC. et al. A Novel STX16 Deletion in autosomal dominant pseudohypoparathyroidism type Ib redefines the boundaries of a cis-acting imprinting control element of GNAS. Am J Hum Genet 2005; 76: 804-814
• 25 Elli FM, De Sanctis L, Peverelli E. et al. Autosomal dominant pseudohypoparathyroidism type Ib: A novel inherited deletion ablating STX16 causes loss of imprinting at the A/B DMR. J Clin Endocrinol Metab 2014; 99: 724-728
• 26 Rezwan FI, Poole RL, Prescott T. et al. Very small deletions within the NESP55 gene in pseudohypoparathyroidism type 1b. Eur J Hum Genet 2015; 23: 494-499
• 27 Chillambhi S, Turan S, Hwang DY. et al. Deletion of the noncoding GNAS antisense transcript causes pseudohypoparathyroidism type Ib and biparental defects of GNAS methylation in cis. J Clin Endocrinol Metab 2010; 95: 3993-4002
• 28 Bastepe M, Fröhlich LF, Linglart A. et al. Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib. Nat Genet 2005; 37: 25-27
• 29 Richard N, Abeguilé G, Coudray N. et al. A new deletion ablating NESP55 causes loss of maternal imprint of A/B GNAS and autosomal dominant pseudohypoparathyroidism type Ib. J Clin Endocrinol Metab 2012; 97: 863-867
• 30 Takatani R, Molinaro A, Grigelioniene G. et al. Analysis of Multiple Families with Single Individuals Affected by Pseudohypoparathyroidism Type Ib (PHP1B) Reveals only One Novel Maternally Inherited GNAS Deletion. J Bone Miner Res 2016; 31: 796-805
• 31 Perez-Nanclares G, Velayos T, Vela A. et al. Pseudohypoparathyroidism type Ib associated with novel duplications in the GNAS locus. PLoS One 2015; 10
• 32 Nakamura A, Hamaguchi E, Horikawa R. et al. Complex genomic rearrangement within the GNAS region associated with familial pseudohypoparathyroidism type 1b. J Clin Endocrinol Metab 2016; 101: 2623-2627
• 33 Grigelioniene G, Nevalainen PI, Reyes M. et al. A Large Inversion Involving GNAS Exon A/B and All Exons Encoding Gsα Is Associated With Autosomal Dominant Pseudohypoparathyroidism Type Ib (PHP1B). J Bone Miner Res 2017; 32: 776-783
• 34 de Lange IM, Verrijn Stuart AA, van der Luijt RB. et al. Macrosomia, obesity, and macrocephaly as first clinical presentation of PHP1b caused by STX16 deletion. Am J Med Genet Part A 2016; 170: 2431-2435
• 35 Turan S, Bastepe M. The GNAS complex locus and human diseases associated with loss-of-function mutations or epimutations within this imprinted gene. Horm Res Paediatr 2013; 80: 229-241
• 36 Linglart A, Maupetit-Méhouas S, Silve C. GNAS-related loss-of-function disorders and the role of imprinting. Horm Res Paediatr 2013; 79: 119-129
• 37 Elli FM, Linglart A, Garin I. et al. The prevalence of GNAS deficiency-related diseases in a large cohort of patients characterized by the EuroPHP network. J Clin Endocrinol Metab 2016; 101: 3657-3668
• 38 Hayward BE, Kamiya M, Strain L. et al. The human GNAS1 gene is imprinted and encodes distinct paternally and biallelically expressed G proteins. Proc Natl Acad Sci 1998; 95: 10038-10043
• 39 Bastepe M. Positional dissociation between the genetic mutation responsible for pseudohypoparathyroidism type Ib and the associated methylation defect at exon A/B: Evidence for a long-range regulatory element within the imprinted GNAS1 locus. Hum Mol Genet 2001; 10: 1231-1241
• 40 De Beur SJ, Ding C, Germain-Lee E. et al. Discordance between genetic and epigenetic defects in pseudohypoparathyroidism type 1b revealed by inconsistent loss of maternal imprinting at GNAS1. Am J Hum Genet 2003; 73: 314-322
• 41 Liu J, Nealon JG, Weinstein LS. Distinct patterns of abnormal GNAS imprinting in familial and sporadic pseudohypoparathyroidism type IB. Hum Mol Genet 2005; 14: 95-102
• 42 Williamson CM, Ball ST, Nottingham WT. et al. A cis-acting control region is required exclusively for the tissue-specific imprinting of Gnas. Nat Genet 2004; 36: 894-899
• 43 Liu J, Chen M, Deng C. et al. Identification of the control region for tissue-specific imprinting of the stimulatory G protein -subunit. Proc Natl Acad Sci 2005; 102: 5513-5518
• 44 Liu J, Litman D, Rosenberg MJ. et al. A GNAS1 imprinting defect in pseudohypoparathyroidism type IB. J Clin Invest 2000; 106: 1167-1174
• 45 Wroe SF, Kelsey G, Skinner JA. et al. An imprinted transcript, antisense to Nesp, adds complexity to the cluster of imprinted genes at the mouse Gnas locus. Proc Natl Acad Sci 2000; 97: 3342-3346
• 46 Eaton SA, Williamson CM, Ball ST. et al. New mutations at the imprinted gnas cluster show gene dosage effects of Gs in postnatal growth and implicate XL s in bone and fat metabolism but not in suckling. Mol Cell Biol 2012; 32: 1017-1029
• 47 Liu J, Yu S, Litman D. et al. Identification of a methylation imprint mark within the mouse Gnas locus. Mol Cell Biol 2000; 20: 5808-5817
• 48 Weinstein LS, Liu J, Sakamoto A. et al. Minireview: GNAS: Normal and abnormal functions. Endocrinology 2004; 145: 5459-5464
• 49 Yang Y, Chu X, Nie M. et al. A novel long-range deletion spanning STX16 and NPEPL1 causing imprinting defects of the GNAS locus discovered in a patient with autosomal-dominant pseudohypoparathyroidism type 1B. Endocrine 2020; 69: 212-219
• 50 Fröhlich LF, Bastepe M, Ozturk D. et al. Lack of Gnas epigenetic changes and pseudohypoparathyroidism type Ib in mice with targeted disruption of syntaxin-16. Endocrinology 2007; 148: 2925-2935
• 51 Cavaco BM, Tomaz RA, Fonseca F. et al. Clinical and genetic characterization of Portuguese patients with pseudohypoparathyroidism type Ib. Endocrine 2010; 37: 408-414
• 52 Chotalia M, Smallwood SA, Ruf N. et al. Pseudohypoparathyroidism: One gene, several syndromes. J Endocrinol Invest 2017; 23: 347-356
• 53 Linglart A, Bastepe M, Jüppner H. Similar clinical and laboratory findings in patients with symptomatic autosomal dominant and sporadic pseudohypoparathyroidism type Ib despite different epigenetic changes at the GNAS locus. Clin Endocrinol (Oxf) 2007; 67: 822-831
• 54 Frohlich LF, Mrakovcic M, Steinborn R. et al. Targeted deletion of the Nesp55 DMR defines another Gnas imprinting control region and provides a mouse model of autosomal dominant PHP-Ib. Proc Natl Acad Sci 2010; 107: 9275-9280
• 55 Mehta S, Williamson CM, Ball S. et al. Transcription driven somatic DNA methylation within the imprinted Gnas cluster. PLoS One 2015; 10: 1-20
• 56 Chotalia M, Smallwood SA, Ruf N. et al. Transcription is required for establishment of germline methylation marks at imprinted genes. Genes Dev 2009; 23: 105-117
• 57 Williamson CM, Turner MD, Ball ST. et al. Identification of an imprinting control region affecting the expression of all transcripts in the Gnas cluster. Nat Genet 2006; 38: 350-355
• 58 Williamson CM, Ball ST, Dawson C. et al. Uncoupling antisense-mediated silencing and DNA methylation in the imprinted Gnas cluster. PLoS Genet 2011; 7: e1001347
• 59 Wang Z, Zang C, Rosenfeld JA. et al. Combinatorial patterns of histone acetylations and methylations in the human genome. Nat Genet 2008; 40: 897-903
• 60 Regha K, Sloane MA, Huang R. et al. Active and repressive chromatin are interspersed without spreading in an imprinted gene cluster in the mammalian genome. Mol Cell 2007; 27: 353-366
• 61 Coombes C, Arnaud P, Gordon E. et al. Epigenetic properties and identification of an imprint mark in the Nesp-Gnasxl Domain of the Mouse Gnas Imprinted Locus. Mol Cell Biol 2003; 23: 5475-5488
• 62 Peters J, Wroe SF, Wells CA. et al. A cluster of oppositely imprinted transcripts at the Gnas locus in the distal imprinting region of mouse chromosome 2. Proc Natl Acad Sci 1999; 96: 3830-3835
• 63 Bastepe M, Gunes Y, Perez-Villamil B. et al. Receptor-mediated adenylyl cyclase activation through XLas, the extra-large variant of the stimulatory G protein α-subunit. Mol Endocrinol 2002; 16: 1912-1919
• 64 Cattanach BM, Kirk M. Differential activity of maternally and paternally derived chromosome regions in mice. Nature 1985; 315: 496-498
• 65 Williamson CM, Beechey CV, Papworth D. et al. Imprinting of distal mouse chromosome 2 is associated with phenotypic anomalies in utero. Genet Res 1998; 72: 255-265
• 66 Plagge A, Gordon E, Dean W. et al. The imprinted signaling protein XLas is required for postnatal adaptation to feeding. Nat Genet 2004; 36: 818-826
• 67 Cattanach BM, Peters J, Ball S. et al. Two imprinted gene mutations: Three phenotypes. Hum Mol Genet 2000; 9: 2263-2273
• 68 Ball ST, Kelly ML, Robson JE. et al. Gene dosage effects at the imprinted Gnas cluster. PLoS One 2013; 8
• 69 Plagge A, Isles AR, Gordon E. et al. Imprinted Nesp55 influences behavioral reactivity to novel environments. Mol Cell Biol 2005; 25: 3019-3026
• 70 Chen M, Gavrilova O, Liu J. et al. Alternative Gnas gene products have opposite effects on glucose and lipid metabolism. Proc Natl Acad Sci USA 2005; 102: 7386-7391
• 71 Mariot V, Maupetit-Méhouas S, Sinding C. et al. A maternal epimutation of GNAS leads to Albright osteodystrophy and parathyroid hormone resistance. J Clin Endocrinol Metab 2008; 93: 661-665
• 72 Unluturk U, Harmanci A, Babaoglu M. et al. Molecular diagnosis and clinical characterization of pseudohypoparathyroidism type-Ib in a patient with mild albrights hereditary osteodystrophy-like features, epileptic seizures, and defective renal handling of uric acid. Am J Med Sci 2008; 336: 84-90
• 73 Mantovani G, De Sanctis L, Barbieri AM. et al. Pseudohypoparathyroidism and GNAS epigenetic defects: Clinical evaluation of Albright hereditary osteodystrophy and molecular analysis in 40 patients. J Clin Endocrinol Metab 2010; 95: 651-658
• 74 Xie T, Plagge A, Gavrilova O. et al. The Alternative Stimulatory G Protein a-Subunit XLas Is a Critical Regulator of Energy and Glucose. Metabolism and Sympathetic Nerve Activity in Adult Mice 2006; 281: 18989-18999