Alternative titles; symbols
ORPHA: 94089; DO: 0080222;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20q13.32 | Pseudohypoparathyroidism Ib | 603233 | Autosomal dominant | 3 | STX16 | 603666 |
| 20q13.32 | Pseudohypoparathyroidism Ib | 603233 | Autosomal dominant | 3 | GNASAS1 | 610540 |
| 20q13.32 | Pseudohypoparathyroidism Ib | 603233 | Autosomal dominant | 3 | GNAS | 139320 |
A number sign (#) is used with this entry because pseudohypoparathyroidism type Ib (PHP Ib) is caused by deletions in the differentially methylated region (DMR) of the GNAS (139320) locus. One deletion (139320.0031) removes the entire NESP55 DMR and exons 3 and 4 of the antisense transcript of the GNAS gene (GNASAS; 610540.0001). PHP1B can also result from deletion in the STX gene (603666), a long-range control element of methylation at the GNAS locus. These methylation and imprinting defects result in the absence of expression of the maternal Gs-alpha isoform.
Pseudohypoparathyroidism refers to a heterogeneous group of disorders characterized by resistance to parathyroid hormone (PTH; 168450). Pseudohypoparathyroidism type Ib is characterized clinically by isolated renal PTH resistance manifest as hypocalcemia, hyperphosphatemia, and increased serum PTH. Biochemical studies show a decreased response of urinary cAMP to exogenous PTH, but normal Gs activity in erythrocytes because the defect is restricted to renal tubule cells. In contrast to the findings in PHP Ia, patients with PHP Ib usually lack the physical characteristics of Albright hereditary osteodystrophy (AHO) and typically show no other endocrine abnormalities, although resistance to thyroid-stimulating hormone (TSH; 188540) has been reported in PHP Ib (Levine et al., 1983, Heinsimer et al., 1984). However, patients with PHP Ib may rarely show some features of AHO (Mariot et al., 2008).
For a general phenotypic description, classification, and a discussion of molecular genetics of pseudohypoparathyroidism, see PHP1A (103580).
Frame et al. (1972) reported 2 patients with renal resistance to parathyroid hormone characterized by hypocalcemia and hyperphosphatemia and associated with osteitis fibrosa cystica. Frame et al. (1972) postulated that renal PTH resistance was the primary defect and that a secondary hyperparathyroid state occurred to cause the skeletal changes of osteitis fibrosa. The calcemic effect of both endogenous and exogenous PTH was blunted by the presence of hyperphosphatemia.
Farfel and Bourne (1980) reported a family in which 5 patients with PHP type I had no signs of AHO and showed normal erythrocyte Gs protein activity.
Kidd et al. (1980) described 3 patients with PHP and bone findings consistent with hyperparathyroidism, including elevated serum alkaline phosphatase and subperiosteal resorption on skeletal films. None of the patients had AHO features of short stature, brachydactyly, or mental deficiency. The authors commented on the paradoxic occurrence of hyperparathyroid bone disease in PHP, and suggested that this was an extreme of a clinical spectrum of skeletal responsiveness to excess PTH.
Heinsimer et al. (1984) found that beta-adrenergic agonist-specific binding properties of red cell membranes were 45% of controls in 5 patients with PHP Ia and 97% of controls in 5 patients with PHP Ib. Further studies were consistent with a single defect causing deficient hormone receptor-nucleotide complex formation and adenylate cyclase activity in PHP Ia, whereas the biochemical lesion(s) appeared not to affect the complex formation in PHP Ib.
Liu et al. (2000) studied 13 patients with PHP Ib, all of whom initially presented with hypocalcemia, hyperphosphatemia, and elevated serum PTH levels in the absence of renal insufficiency or any of the clinical or radiologic features of Albright hereditary osteodystrophy. Serum thyrotropin (TSH), thyroxine (T4), free T4, triiodothyronine (T3), and 25-hydroxyvitamin D levels were normal in all patients. Two patients had overt osteitis fibrosa cystica at presentation that resolved with oral calcium and vitamin D therapy. Two other patients had at least 1 other affected family member.
Clinical Variability
De Nanclares et al. (2007) reported 4 unrelated patients who were thought to have PHP1A because of PTH and TSH resistance and mild features of Albright hereditary osteodystrophy. Two patients showed decreased G-alpha activity in erythrocytes. However, genetic analysis did not reveal germline point mutations in the GNAS gene in any of the patients; instead, all were found to have GNAS methylation defects, which are usually associated with PHP1B. Furthermore, 1 of the patients with normal G-alpha activity was found to have a 3.0-kb STX16 deletion (603666.0001), which is usually associated with PHP1B. The findings suggested that there may be an overlap between the molecular and clinical features of PHP1A and PHP1B, and that methylation defects may manifest as mild PHP1A.
Mariot et al. (2008) reported a girl with obvious Albright osteodystrophy features, PTH resistance, and normal G-alpha-s bioactivity in red blood cells (PHP Ib), yet no loss-of-function mutation in the GNAS coding sequence. The patient had broad methylation changes at all differentially methylated regions of the GNAS gene leading to a paternal epigenotype on both alleles. Mariot et al. (2008) suggested that Albright osteodystrophy features are not specific to PHP Ia, and concluded that the decreased expression of G-alpha-s due to GNAS epimutations is not restricted to the renal tubule but may affect nonimprinted tissues like bone. PHP1B should be considered a heterogeneous disorder that should lead to the study of GNAS epigenotype in patients with PHP and no mutation in GNAS exons 1 through 13, regardless of their physical features.
Lecumberri et al. (2010) reported a patient with PHP1B who had paternal uniparental isodisomy of chromosome 20q. However, he also had mild features of AHO and cognitive impairment, suggestive of PHP1A. Erythrocyte Gs-alpha activity was slightly decreased at 81% of control values.
PHP Ib is most often a sporadic disorder, but sex-influenced autosomal dominant inheritance has been reported. In familial cases, PTH resistance in PHP1B develops only after maternal inheritance of the molecular defect, whereas paternal inheritance of the defect is not associated with PTH resistance. This is the same situation as in PHP1A and PPHP (612463) (Mantovani and Spada, 2006).
By analysis of 4 families with PHP1B, Juppner et al. (1998) showed that the genetic defect is imprinted paternally, meaning that the disorder only occurs if the defective gene is inherited from a female carrier. Offspring of an affected father were unaffected.
Lecumberri et al. (2010) reported 2 unrelated families in which PHP1A and PHP1B occurred coincidentally within different branches of each of the families. In the first family, 2 sibs with PHP1A inherited a GNAS mutation from their affected mother. A man from another branch of the family with PHP1B was found to have paternal uniparental isodisomy of chromosome 20q, with presumed lack of expression of the maternal allele. The diagnosis was confusing in this patient before molecular analysis because he had mild features of AHO and cognitive impairment, suggestive of PHP1A. Genetic analysis confirmed that he did not have a germline GNAS mutation. In the second family, 1 individual with PHP1A had a GNAS mutation (139320.0011) inherited from his mother, and a second cousin had PHP1B with an epigenetic defect at the GNAS locus. Lecumberri et al. (2010) emphasized the importance of molecular diagnosis for proper genetic counseling.
Juppner et al. (1998) performed a genomewide search using genomic DNA from 4 kindreds with PHP Ib and established linkage to a small telomeric region on chromosome 20q (20q13.3), which contains the GNAS1 gene. However, no gross deletions or rearrangements of the GNAS gene were detected by Southern blot analysis. Juppner et al. (1998) postulated that mutations in a promoter or enhancer of the GNAS gene could explain the kidney-specific resistance toward PTH and the resulting hypocalcemia in patients with PHP Ib.
PHP Ib is caused by methylation and imprinting defects of the maternal GNAS gene with subsequent loss of expression of the Gs-alpha protein in renal proximal tubules. Since only the maternal allele, and not the paternal allele, is expressed in renal tubule cells, the defect results in complete lack of Gs-alpha activity in these cells. Patients with PHP1B do not have mutations within GNAS exons that encode the Gs-alpha isoform (Mantovani and Spada, 2006; Bastepe, 2008).
Hayward et al. (1998) found that a splice variant of the GNAS1 gene, XL-alpha-s (Kehlenbach et al., 1994), is transcribed from the paternal allele only, providing further confirmation that the chromosomal region that comprises the GNAS locus undergoes imprinting. The authors noted that if GNAS transcripts are derived, at least in some tissues or cells, from only 1 parental allele, mutations in a promoter or enhancer of the GNAS gene could explain the kidney-specific resistance toward PTH and hypocalcemia in patients with PHP Ib.
Zheng et al. (2001) noted that kindred studies in PHP Ib suggested that the cause of isolated renal resistance to PTH is a specific decrease in Gs-alpha activity in renal proximal tubules due to paternal imprinting of Gs-alpha. However, using RT-PCR assays, Zheng et al. (2001) found that Gs-alpha transcripts were biallelically expressed in human fetal kidney cortex. The results were in contrast to the parent-specific expression of exon 1A and XL-alpha-s (paternal) or NESP (maternal) mRNAs. The authors concluded that PHP1B is not due to paternal imprinting of Gs-alpha within the renal proximal tubule, and proposed that maternal inheritance of abnormal imprinting of upstream GNAS1 exons might be responsible for PHP1B. However, Liu et al. (2000) stated that Gs-alpha is biallelically expressed in all fetal tissues.
Using hot-stop PCR analysis on total RNA from 6 normal human thyroid specimens, Liu et al. (2003) showed that the majority of the Gs-alpha mRNA (72 +/- 3%) was derived from the maternal allele. Patients with PHP Ib have an imprinting defect of the Gs-alpha gene resulting in both alleles having a paternal epigenotype, which would lead to a more moderate level of thyroid-specific Gs-alpha deficiency. The authors found evidence of borderline TSH resistance in 10 of 22 PHP Ib patients. The authors concluded that their study provided further evidence for tissue-specific imprinting of Gs-alpha in humans with a potential mechanism for borderline TSH resistance in some patients with PHP Ib.
Liu et al. (2000) showed that the human GNAS exon 1A promoter region, located 2.5 kb upstream from exon 1 of the Gs-alpha transcript, is within a differentially methylated region (DMR) and is imprinted in a manner similar to that in the mouse: the region is normally methylated on the maternal allele and unmethylated on the paternal allele. In 13 patients with PHP1B, Liu et al. (2000) found that the exon 1A region of GNAS was unmethylated on both alleles, consistent with an imprinting defect. The authors proposed that the exon 1A DMR is important for establishing or maintaining tissue-specific imprinting of Gs-alpha, and that paternal-specific imprinting of exon 1A on both alleles would reduce Gs-alpha expression specifically in renal proximal tubules, which only express Gs-alpha from the maternal allele.
In affected individuals in 9 unrelated kindreds with PHP Ib, Bastepe et al. (2001) found loss of methylation at GNAS1 exon 1A, which they called exon A/B. Further genetic analysis of the largest PHP Ib kindred revealed that the mutation leading to the disease, and presumably to the methylation defect at exon 1A, most likely resided in untranscribed GNAS1 sequences 56 kb centromeric to exon 1A.
Bastepe et al. (2001) reported a patient with PHP Ib who had paternal uniparental isodisomy of chromosome 20q and lacked the maternal-specific methylation pattern within GNAS1. There was no impairment of Gs-alpha activity in fibroblasts. The authors suggested that loss of the maternal GNAS1 gene and the resulting epigenetic changes alone could lead to PTH resistance in the proximal renal tubules.
Jan de Beur et al. (2003) analyzed allelic expression and epigenetic methylation of CpG islands within exon 1A of GNAS1 in patients with sporadic PHP Ib and in affected and unaffected individuals from 5 multigenerational kindreds with familial PHP Ib. All subjects with PTH-resistance showed loss of methylation of the exon 1A region on the maternal GNAS1 allele and/or biallelic expression of exon 1A-containing transcripts, consistent with an imprinting defect. Paternal transmission of the disease-associated haplotype was associated with normal patterns of GNAS1 methylation and PTH responsiveness. In 1 kindred, affected and unaffected sibs had inherited the same GNAS1 allele from their affected mother, indicating dissociation between the genetic and epigenetic GNAS1 defects. The absence of the epigenetic defect in subjects who inherited a defective maternal GNAS1 allele suggested that the genetic mutation may be incompletely penetrant and indicated that the epigenetic defect, not the genetic mutation, leads to renal resistance to PTH in PHP Ib.
In affected members and obligate carriers of 12 unrelated families with PHP Ib, Bastepe et al. (2003) identified a heterozygous 3-kb microdeletion located approximately 220 kb centromeric of exon 1A of the GNAS gene. The deletion also included 3 of 8 exons encoding syntaxin-16 (603666.0001). However, Bastepe et al. (2003) considered the involvement of STX16 in the molecular pathogenesis of PHP Ib unlikely. They postulated that the microdeletion disrupts a putative cis-acting element required for methylation at exon 1A in the GNAS locus, and that this genetic defect underlies the pathogenesis of PHP Ib. Four of 16 apparently sporadic patients also had the deletion. Affected individuals with the microdeletion showed loss of exon 1A methylation, but no other epigenetic abnormalities. In all examined cases, the deletion was inherited from the mother, consistent with the observation that PHP Ib develops only in offspring of female obligate carriers.
In all affected individuals and obligate carriers in a large kindred with PHP Ib, Linglart et al. (2005) identified a 4.4-kb microdeletion overlapping with a region of the 3-kb deletion identified by Bastepe et al. (2003). Affected individuals exhibited loss of methylation only at GNAS exon A/B. Linglart et al. (2005) concluded that PHP Ib comprises at least 2 distinct conditions sharing the same clinical phenotype: one associated with the loss of exon A/B methylation alone and, in most cases, with a heterozygous microdeletion in the STX16 region, and the other associated with methylation abnormalities at all GNAS DMRs, including the DMR at exon A/B.
Among 20 unrelated PHP Ib probands, Liu et al. (2005) found that all had loss of GNAS exon 1A imprinting (a paternal epigenotype on both alleles). All 5 probands with familial disease had a deletion mutation within the closely linked STX16 gene and a GNAS imprinting defect involving only the exon 1A region. In contrast, the STX16 mutation was absent in all sporadic cases. The majority of these patients had abnormal imprinting of the more upstream regions in addition to the exon 1A imprinting defect, with 8 of 15 having a paternal epigenotype on both alleles throughout the GNAS locus. In virtually all cases, the imprinting status of the paternally methylated NESP55 and maternally methylated NESPAS/XL-alpha-s promoters was concordant, suggesting that their imprinting may be coregulated, whereas the imprinting of the NESPAS/XL-alpha-s promoter region and XL-alpha-s first exon was not always concordant, even though they are closely linked and lie within the same DMR. The authors concluded that familial and sporadic forms of PHP Ib have distinct GNAS imprinting patterns that occur through different defects in the imprinting mechanism.
In affected members of 2 unrelated kindreds with PHP Ib who lacked STX16 mutations or deletions, Bastepe et al. (2005) identified heterozygosity for a 4.7-kb deletion that removed the DMR of the GNAS gene encompassing the NESP55 region and exons 3 and 4 of the GNAS antisense transcript (GNASAS) (see 139320.0031 and 610540.0001). When inherited from a female, the deletion abolished all maternal GNAS imprints and derepressed maternally silenced transcripts, suggesting that the deleted region contains a cis-acting element that controls imprinting of the maternal GNAS allele.
Mantovani et al. (2007) studied GNAS differential methylation and STX16 microdeletions in genomic DNA from 10 Italian patients with sporadic PHP Ib. Molecular analysis showed GNAS cluster imprinting defects in all of the patients, only one of whom had a de novo STX16 deletion. All of the patients were resistant to TSH, and all but 1 maintained normal responsiveness to GHRH.
Variability
In 3 brothers with a clinical diagnosis of PHP Ib, Wu et al. (2001) identified heterozygosity for a 3-bp in-frame deletion in exon 13 of the GNAS gene (ile382del; 139320.0033), resulting in an amino acid change in the C terminus of the protein. The boys had hypocalcemia, increased serum PTH, lack of cAMP response to PTH, and normal erythrocyte Gs activity. When expressed in vitro, the mutant Gs-alpha was unable to interact with the PTH receptor (PTHR1; 168468) but showed normal coupling to other coexpressed heptahelical receptors. The findings were consistent with isolated PTH resistance. Although the mother and maternal grandfather also carried the mutation, they had no evidence of PTH resistance, consistent with a model of paternal imprinting of the locus.
Linglart et al. (2002) identified a heterozygous nonsense mutation in exon 13 of the GNAS gene (Y391X; 139320.0036) in a girl with a clinical diagnosis of PHP1C (612462). She had PTH resistance, multiple hormone resistance, and the physical features of Albright hereditary osteodystrophy. Biochemical studies showed decreased cAMP response to PTH and normal erythrocyte cAMP activity. The mutation terminated the Gs-alpha isoform only 4 amino acids before the wildtype stop codon, and was shown to interrupt receptor coupling while retaining adenylyl cyclase activity. The retention of erythrocyte Gs-alpha activity and lack of cAMP response to PTH associated with a mutation in the C-terminal receptor-coupling domain of Gs-alpha was similar to that observed in the patient reported by Wu et al. (2001).
Although the selective resistance toward a single hormone (PTH) in PHP Ib suggested inactivating mutations in the receptor for PTH, a considerable number of PHP Ib patients were found to have no mutations in the coding or noncoding exons of the PTHR1 (168468) gene (Schipani et al., 1995; Bettoun et al., 1997). Furthermore, analysis of PTHR1 mRNA provided no evidence for splice variants that could have offered an explanation for the disorder (Suarez et al., 1995). Inactivating mutations in the PTHR1 gene were found in patients with the Blomstrand type of lethal metaphyseal chondrodysplasia (215045).
Fukumoto et al. (1996) reported reduced expression of the 2.4-kb PTH/PTHrP receptor mRNA in 2 patients with PHP type Ib and higher levels in a third. Reduced expression was also reported by Suarez et al. (1995). Fukumoto et al. (1996) suggested that while lower levels of PTH/PTHrP receptor transcript may explain the resistance to PTH in some PHP type Ib patients, this cannot be a general mechanism.
Jan de Beur et al. (2000) used polymorphic markers in or near the genes encoding PTH and its receptors to perform linkage analysis between these loci and PHP1B. They found no linkage between the PTH gene or the PTH receptor genes and PHP1B.
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