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Department of Pediatric Endocrinology (A.L., J.C.C.), Groupe Hospitalier Cochin-Saint Vincent de Paul, Assisvance Publique-Hôpitaux de Paris, 75014 Paris, France; Centre National de la Recherche Scientifique Unity 1524 (M.G.), Groupe Hospitalier Cochin-Saint Vincent de Paul, 75014 Paris, France; Department of Biochemistry (T.L., M.L.K.), Unity of Molecular Genetics, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, 75013 Paris, France; Department of Pediatrics (E.M.), 76000 Rouen, France; Departmènt of Genetics and Reproduction (M.L.K.), Centre Hospitalo-Universitaire, 14033 Caen, France
Address all correspondence and requests for reprints to: Prof. Marie-Laure Kottler, Département Génétique et Reproduction, Hôpital Clémenceau, 14033 Caen, France. E-mail: kottler-ml{at}chu-caen.fr
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Abstract |
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subunit of Gs (GNAS1) in 30 subjects (21 unrelated families) with Albright’s hereditary osteodystrophy (AHO), pseudohypoparathyroidism (PHP); and decreased erythrocyte Gs activity (PHP-Ia; n = 19); AHO and decreased erythrocyte Gs activity (isolated AHO; n = 10); or AHO, hormonal resistance, and normal erythrocyte Gs activity (PHP-Ic; n = 1). A heterozygous GNAS1 gene lesion was found in 14 of 17 PHP-Ia index cases (82%), including 11 new mutations and a mutational hot-spot involving codons 189–190 (21%). These lesions lead to a truncated protein in all but three cases with missense mutations R280K, V159M, and D156N. In the patient diagnosed with PHP-Ic, Gs protein was shortened by just four amino acids, a finding consistent with the conservation of Gs activity in erythrocytes and the loss of receptor contact. No GNAS1 lesions were found in individuals with isolated AHO that were not relatives to PHP-Ia patients (n = 5). Intrafamilial segregation analyses of the mutated GNAS1 allele in nine PHP-Ia patients established that the mutation had either occurred de novo on the maternal allele (n = 4) or had been transmitted by a mother with a mild phenotype (n = 5). This finding is consistent with an imprinting of GNAS1 playing a role in the clinical phenotype of loss of function mutations and with a functional maternal GNAS1 allele having a predominant role in preventing the hormonal resistance of PHP-Ia. |
Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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is one of the subunits inducing the stimulation of adenylyl cyclase (AC) (2) and the production of cAMP as a second messenger. Gs has two main domains, GTPase and helical. Receptor interaction occurs at the C-terminal end, in the GTPase domain (3).
Deficiency of the protein Gs has been associated with heterogeneous clinical manifestations. Although resistance to PTH [pseudohypoparathyroidism (PHP)] was the first reported feature, further studies revealed resistance to other hormones (TSH, gonadotropins, glucagon, epinephrine) (4, 5, 6, 7) as well as Albright’s hereditary osteodystrophy (AHO), a constellation of manifestations including short stature, obesity, rounded face, mental retardation, sc ossifications, and characteristic shortening and widening of long bones in the hands and feet (brachydactyly) (OMIM no. 103580; for review, see Refs.8 and 9). The Gs biological activity is generally decreased in erythrocytes or fibroblasts of affected individuals (10). In addition, some patients have been identified with isolated features of AHO in the absence of hormonal resistance.
Genetic analysis has revealed heterozygous loss of function mutations in GNAS1, the gene encoding Gs (11, 12, 13, 14, 15, 16, 17, 18, 19), transmitted as an autosomal dominant trait with apparently incomplete penetrance. GNAS1 contains 13 exons encoding Gs, 12 introns spanning 20 kb, and maps to 20q13 (20). Recently, three additional transcripts (21, 22, 23) were described, each having distinct first exons under the control of specific promoters that are differentially methylated. Two of these alternative transcripts encode different proteins: Xls (21), a Golgi-specific isoform of Gs, and NESP55 (22), a neurosecretory protein.
Several questions remain unresolved, including the role of the different mutations of GNAS1 in various clinical phenotypes observed (genotype-phenotype correlation) and the basis for the extreme variability of the clinical phenotype among relatives harboring the same mutation. Indeed, in a same kindred, patients with GNAS1 mutation present with or without hormonal resistance. The observation in a knock-out model of tissue-specific paternal imprinting of Gnas, the mouse homologue of GNAS1 (24), as well as pedigree analysis of affected families, suggests the role of genomic imprinting (25).
To address these questions, we conducted a thorough clinical and biological study in a large group of patients with Gs deficiency, including genetic analysis and study of intrafamilial transmission of disease-associated GNAS1 alleles.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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We studied 21 index cases from 21 unrelated families and 9 affected siblings (Fig. 1
). Inclusion criteria in the study were: 1) PHP associated with decreased erythrocyte Gs activity (PHP-Ia; n = 19); 2) clinical features suggesting AHO associated with decreased erythrocyte Gs activity without PTH resistance (isolated AHO; n = 10); or 3) one patient (patient 11c) with PHP, multiple hormonal resistance, AHO but normal erythrocyte Gs activity, an association generally referred to as PHP-Ic (9). Among the patients with isolated AHO, five were relatives of PHP-Ia patients, and five had sporadic AHO.
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Overt PTH resistance was defined by a low serum calcium concentration (<2.19 mmol/liter), a high serum phosphate concentration (>1.2 mmol/liter), and an increased serum level of PTH (>60 ng/ml). Compensated PTH resistance was defined as elevated serum PTH with normal serum calcium. In seven subjects (including those with compensated PTH resistance), the absence of urinary cAMP rise after exogenous PTH stimulation further confirmed the resistance. TSH resistance was defined by increased TSH level (>5 µU/ml) on at least two different measurements, irrespective of fT4 levels. To analyze the responsiveness to gonadotrophins, LH, FSH, T, or E2 concentrations were measured in 17 patients.
Quantitative analysis of the Gs protein biological activity
The procedure is adapted from that used by Levine et al. (10) and is based on the measurement of cAMP generated after AC reconstitution of human erythrocyte membranes with turkey erythrocyte membranes (that lack Gs). Heparinized blood samples were collected, and erythrocyte membranes were prepared by ultracentrifugation. Then, Gs proteins were extracted. Gs was activated by a nonhydrolyzable GTP-analog (GTP 
s) that maintains Gs in its active form after reconstitution with turkey erythrocyte membranes. In vitro-generated cAMP was measured using a Pasteur RIA kit, and results were expressed as percentage of the mean of three normal samples. In addition, two known pooled erythrocyte membrane samples were used as controls. Interassay coefficient of variation for Gs activity ranged between 8 and 11%. Values less than 85% were considered as decreased.
Molecular analyses
All patients and families gave their informed consent for collection of DNA and molecular studies.
Genomic DNA was extracted from peripheral leukocytes. We designed seven sets of primers for amplification of exons 2–13 of GNAS1 gene and intron-exon junctions from published sequences (20). For exon 1 and its boundaries, two sets of primers (a and b) were designed a sense 5'-TCCTTGCCGAGGAGCCGAG-3', a antisense 5'-CCCTTACCCAGCAGCAGCAGGC-3', b sense 5'-AAGGCGCAGCGTGAGGCCAAC-3', b antisense 5'-CTGCGGGGCGCCCTTCGAG-3'. PCRs were performed by standard techniques. After electrophoresis on agarose or polyacrylamide, the PCR products were purified on Microcon-100 columns (Amicon, Beverly, MA), and both DNA strands were sequenced on an ABI PRISM 377 DNA Sequencer (PE Applied Biosystems, Roissy, France). Restriction analysis was used, when informative, for intrafamilial segregation analysis with the appropriated enzymes.
Concerning the de novo mutations, parental origin of the mutated alleles was studied by amplifying a long genomic PCR fragment (Expand Long Template PCR System, Roche Diagnostics, Meylan, France) of the index case comprising both the GNAS1 genetic lesion and an informative familial polymorphism. To separate alleles from paternal and maternal origin, PCR products were subcloned using the TOPO-TA Cloning kit (Invitrogen, San Diego, CA). Then, independent clones (about 15) were chosen at random and sequenced. Each clone being differentially tagged by the familial polymorphism, sequencing allows us to determine whether the mutation was on the maternal or paternal allele (Fig. 3).
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Figure 1
shows the pedigrees of the 21 families, and clinical and biochemical details for each proband are given in Tables 1 and 2. In the 20 patients (17 families) with PHP-Ia or Ic, the sex ratio of the affected subjects was 1, and the mean age at diagnosis was very variable, ranging from birth to 60 yr (median, 8.9 yr). In 45% of cases, hypocalcemic symptoms led to the diagnosis. Short stature was found in 7 cases (35%), obesity in 16 cases (80%). Fourteen subjects had overt PTH resistance with hypocalcemia requiring 1- hydroxylated vitamin D derivatives. Six had compensated PTH resistance (normal calcemia and increased PTH), and four of these were treated with vitamin D derivatives. Short fourth and fifth metacarpal and round-shaped face were present in 95 and 90%, respectively, of patients with PHP. TSH resistance was present in 19 of 20 patients (95%) investigated. Other causes of subclinical hypothyroidism (autoimmune thyroid disease) were ruled out. Unequivocal gonadotropin resistance characterized by decreased testicular volume, low free T, and elevated basal and GnRH-stimulated FSH and LH was found in a 60-yr-old male (patient 8c) (Table 3). Three girls (patients 7c, 11c, and 13c) had increased plasma gonadotrophin levels measured at ages 7.5, 14, and 1.5 yr. However, patients 7c and 11c went through puberty uneventfully. Among the 20 patients with PHP-Ia, six were older than 20 yr at the time of the study, and two of these (patients 7c and 16c) have had two children and one child, respectively. The biological activity of Gs measured in erythrocyte membranes ranged from 43–75% of normal in this group (mean, 58%), except for the PHP-Ic patient (108%).
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). Five were mothers of PHP-Ia patients and were identified during the familial survey. Their mean age at diagnosis was 29.3 yr, and they presented, in general, few signs of AHO. They were short in stature (height SD score, -1.3), and three were overweight (6b, 7a, and 14b). Three of them (60%) had sc calcifications, but none had short metacarpal or evident dysmorphic features. The five other patients presented with short stature (-2.5 SD in average) and isolated signs of AHO. They did not exhibit PTH or TSH resistance, but three of three tested had decreased erythrocyte Gs activity (mean, 56%; range, 44–75%). Molecular analysis of the GNAS1 gene
Fourteen heterozygous mutations, scattered in the GNAS1 gene, were identified in the 17 families (82%) with PHP-Ia (Fig. 2). These genetic alterations comprise deletions (n = 5), single nucleotide insertion (n = 1), splice junction mutations (n = 2), missense mutations (n = 3), and nonsense mutations (n = 3). Eleven of these gene lesions have not been previously described to our knowledge, and the three others (21%) are located in the hot-spot site in codon 189–190 of exon 7 (16). Despite an extensive study of sequencing results, no mutation was found in three families with a typical PHP-Ia proband (families 15, 16, and 17; for clinical details, see Table 1).
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Insertion. A 4-bp CCAG insertion in codon 262 of exon 10 was found in the PHP-Ia proband of family 12. His mother, with an isolated AHO phenotype, also carries this insertion. Because of a frameshift and a premature termination codon, the altered protein is expected to have only the first 300 amino acids of the wild type.
Splice junction mutations.
Two substitutions (G
C and AG) of the acceptor splice site at the 3' end of introns 6 and 9, respectively, were found in PHP-Ia probands of kindreds 3 and 8 and confirmed by AluI and FokI restriction patterns. As expected from clinical phenotypes, subject 3c was the only carrier of the mutation in her family. Family members in family 8 could not be investigated.
Nonsense mutations. A nonsense mutation, replacing a tryptophan by a stop codon at residue 154 in exon 6 (W154X), was found in the two PHP-Ia affected daughters and in their mother with isolated AHO in kindred 9. Another nonsense mutation at residue 342 (R342X) was identified in the PHP-Ia proband of family 10, but not in her unaffected parents and siblings.
In family 11, the proband, with normal Gs activity (PHP-Ic), had a nonsense mutation of codon 391 in exon 13 (Y391X), only 4 amino acids before the wild-type stop codon.
Missense mutations.
A GC transversion resulting in an Arg to Lys substitution at residue 280 (R280K) in exon 10 was identified in patient 1c. Arg280 is located within the 3/ß5 region that interacts with the AC (26, 27, 28). In the proband of family 4, we identified an AG transition at residue 159 of exon 6, creating a new BsmI restriction polymorphism and resulting in a Val to Met substitution (V159M). A GA transition resulting in an Asp to Asn replacement at residue 156 (D156N) was identified in the PHP-Ia proband of family 13. Her three siblings and parents did not carry the mutation, although the parents had borderline Gs activity (73 and 79%).
Patients with isolated AHO. No mutation was found in the five subjects with isolated AHO and decreased Gs activity.
Polymorphisms. We also identified two new polymorphisms in the noncoding sequence: c-t transitions 17 bp and 128 bp upstream exon 6 and exon 13, respectively, and a conservative C-T substitution of residue 185 in exon 7 creating a new MseI restriction site previously described as abolishing a BclI restriction site (29). The latter polymorphism was undetectable in 50 anonymous DNA samples, indicating its low frequency.
Genotype-phenotype correlations
Within families, there was a good concordance between clinical phenotypes, between affected siblings (families 6, 9, and 14), all of them exhibiting PTH and TSH resistance. However, although bearing the same mutation (families 6, 7, 9, 12, and 14), mothers were less affected, displaying no sign of hormonal resistance. They appear to have pseudo-pseudohypoparathyroidism.
In 11 families with a mutation resulting in a premature stop codon and truncated protein, the proband had a severe multihormonal resistance phenotype. Phenotype appeared milder in two cases with substitutive mutations. Patient 1c, with R280K mutation, had isolated PTH resistance but no TSH resistance, although he is 41 yr old and was followed for 29 yr. Similarly, patient 4c (V159M) had AHO and TSH resistance but compensated PTH resistance, although he is now 22 yr old. However, patient 13c (D156N) was diagnosed at 1 yr with TSH resistance and developed PTH resistance soon afterward.
Last, we did not observe any relationship between the erythrocyte Gs activity and either the nature of the molecular lesion or the phenotype.
Intrafamilial transmission of the mutated allele
Segregation analysis indicated that of the 14 GNAS1 mutations identified in PHP, 7 had occurred de novo, 5 were maternally transmitted, and none were paternally transmitted. Transmission could not be determined in two cases, in the absence of parental DNA samples.
With respect to de novo mutations, we sought to determine whether they had preferentially occurred on one of the parental alleles. In four of seven families, we identified a polymorphism that was informative for segregation analysis and could apply to the strategy described in Patients and Methods and illustrated in Fig. 3 for family 5. The patient had a de novo 4-bp deletion in exon 7 and was informative for a Fok1 polymorphism in exon 5. A large DNA fragment including exons 5 and 7 was amplified. PCR products included alleles of both paternal (50%) and maternal (50%) origin, which were separated after subcloning. Five clones were tested. Clones 2 and 4 had the deletion and were Fok1 negative, whereas clones 1, 3, and 5 were Fok1 positive without the deletion. Because the Fok1-positive polymorphism was transmitted by the father, we concluded that the deletion was located on the maternal allele. A similar strategy was applied in three other cases. In all four cases, we found that de novo mutations had occurred on the maternal allele (Table 4).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Genetic lesions were observed in 14 of 17 (82%) index cases with PHP-Ia phenotype and Gs deficiency. In contrast with activating mutations, limited to codons 201 and 227 (30), the identified mutations were scattered throughout the GNAS1 gene, occurring however predominantly in exons 6 (3 of 14) and 7 (4 of 14), in particular at codons 188–190, as previously described (15, 16, 17), and in exon 10 (3 of 14). They resulted in the putative production of a truncated protein in the majority (11 of 14) of cases. Although we did not perform functional studies, we believe that these 14 mutations are causal in the disease phenotype for several reasons. First, when we have analyzed siblings, there was perfect concordance between the presence of the mutation and the PHP-Ia phenotype. Second, mutations leading to a truncated protein are expected to produce proteins that lack some of the domains that are crucial for biological activity, including the carboxyl terminus that is required for receptor coupling. Third, the three-point mutations identified substitute key amino acids for the biological activity of the protein. R280 belongs to the 3/ß5 region that interacts with AC (26, 28, 31, 32). Replacement of five s residues in the 3/ß5 loop by five i homologs, including a R280K substitution, decreases in vitro ß2-adrenergic receptor-mediated AC activation of Gs, increasing however the apparent affinity of Gs for the receptor (28). R280 may also influence the interaction with ß (28). It would be of interest to investigate whether there are receptor-specific coupling defects because our patient had PTH resistance but no TSH resistance.
V159M and D156N substitutions alter amino acids that are widely conserved across species and located in the D loop, which is in contact with switch III of the GTPase domain. The proper position of these two domains plays an important role in allowing receptor actions (33, 34). Mutation of D158 was shown to reduce the responsiveness to receptor stimulation (33). However, we cannot also exclude that the functional defects are due to folding and/or expression problems. Western blot could be used to assess Gs protein expression.
The nonsense mutation (Y391X) is particularly interesting because it was identified in a patient with AHO and multihormonal resistances and normal erythrocyte Gs activity. Patients with similar phenotype have been identified in the literature and classified as PHP-Ic (9). The mutated gene that was identified encodes a truncated protein deleted in the four last residues. Studies using carboxyl-terminal peptides (35) or minigene approaches (36) have shown that residues 384–394 are important for receptor-mediated cellular response. We suggest that in patient 14c Gs-receptor interaction is lost, thus explaining the hormonal resistance, whereas AC stimulation (evaluated in the present Gs bioassay) is conserved (14). This mutation underlines the limits of the Gs biological assay we have used which is not dependent on receptor-mediated activation. If we had used an erythrocyte assay examining receptor-stimulated Gs activation (GTP and isoproterenol) the Gs defect would most likely be evident, and we would have probably classified this patient as having PHP-Ia.
We could not find clinical or biological heterogeneity between the PHP-Ia patients with and without GNAS1 gene mutation. Several explanations can be envisioned for the failure to detect a GNAS1 gene mutation in three (15%) patients with PHP-Ia. First, the molecular defect could lie on the beginning of exon 1, which was difficult to amplify because of its high GC nucleotides content (20). Second, other regions of the GNAS1 gene such as promoter or regulatory sequences or other genes regulating Gs expression could be involved. Third, because Gs activity was evaluated on a membrane extract, we could propose a Gs inhibitor within the membrane. Biochemical evaluation of the Gs expression, using immunoblots for instance, is required to progress in the understanding of these alterations. We can hypothesize that normal Gs protein expression and the absence of a mutation in the coding regions makes the presence of a GNAS1 molecular defect unlikely.
The most intriguing features in PHP-Ia are the severe loss of function phenotype associated with heterozygous mutations and the variation of phenotype (with or without hormonal resistance) between generations, sometimes interpreted as variable penetrance. We observed, in nine informative families, that patients with hormonal resistance always had a mutation on the maternal allele: four de novo mutations and five maternally transmitted mutations. This bias for the occurrence of mutations on the maternal allele suggests that mutations inherited from the father, or occurring on the paternal allele, are associated with a mild phenotype, as observed in mothers of severely affected patients. Unfortunately, we could not test this hypothesis directly by determining the parental origin of mutated alleles in mothers with AHO phenotype without hormonal resistance. Using mice as a model, Yu et al. (24) clearly demonstrated a paternal imprinting of Gs in specific tissues, leading to expression from the maternal allele. Similarly, genomic imprinting has been shown to play an important part in the complicated regulation of transcription in the GNAS1 gene complex (21, 22, 23). This suggests that in humans, paternal imprinting of the Gs is an important mechanism in the variation of phenotypic expression of the mutations, as previously observed in diseases such as Prader-Willi and Angelman syndrome (37). Recently, Hayward et al. (38) have shown that Gs is monoallelically expressed from the maternal allele in the normal adult pituitary, thus consistent with a paternal imprinting in this tissue.
In addition, all hormones that activate Gs are not similarly affected by GNAS1 mutations; the resistance affects PTH, TSH, epinephrine, and to some extent gonadotropins, but not vasopressin signaling. In the mouse, the paternal imprinting phenomenon was found to be tissue-specific (24). We found a similar 50% reduction in erythrocyte Gs activity in both AHO mothers and PHP-Ia children harboring the same mutation, suggesting that GNAS1 expression is biallelic in the erythroid lineage, as previously shown by others (39).
The identification of pauci-symptomatic individuals in families of severe PHP-Ia patients makes plausible that individuals with isolated AHO exist outside of the severely affected families. In that respect, we screened such patients with decreased Gs biological activity for GNAS1 gene mutation. However, no GNAS1 gene lesion was found. Similar findings were recently reported in Italian patients (40), suggesting another pathogenic mechanism. In family 18, AHO alone with decreased Gs activity was passed down maternally, which contradicts the imprinting, further suggesting that the defect is not in GNAS1 in this family. Further biochemical and molecular investigations on similar patients are needed to understand the decrease in Gs activity.
Finally, it is important to evaluate whether the genetic testing of PHP-Ia patients would improve the clinical care of either patients or their relatives. In 51% of PHP-Ia, hypocalcemic symptoms, often revealed by seizures, lead to the diagnosis (41), and the identification of siblings with GNAS1 mutations could allow their close follow-up. Although we did not fully address this question, this was demonstrated in patient 14d, who, at age 3 months had compensated PTH and TSH resistance and was clinically asymptomatic. We could also exclude definitely the diagnosis in siblings in other families.
Our conclusions from these studies are as follows. First, PHP-Ia patients have GNAS1 mutations on the maternal allele. Second, patients classified as PHP-Ic because of a normal erythrocyte Gs activity, based on cAMP measurement, should be screened for GNAS1 gene mutations because the analysis of one such patient revealed a truncation of the protein consistent with the loss of receptor Gs coupling with preservation of AC-stimulating activity. This classification may be prevented by using an assay that measured receptor-mediated Gs signaling (using GTP and isoproterenol). Third, we did not find GNAS1 mutations in a small number of sporadic cases with isolated AHO. However, analysis of PHP-Ia families shows that individuals with isolated AHO and GNAS1 lesions exist (so-called pseudopseudohypoparathyroidism). Identification of such individuals (especially if female) has important prognostic implications for genetic counseling. Therefore, GNAS1 molecular analysis should be performed in patients with isolated AHO phenotype, although other pathogenic mechanisms are involved in a majority of cases.
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Acknowledgments |
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Footnotes |
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Received December 21, 2000.
Accepted September 24, 2001.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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-subunit (Gs) knockout mice is due to tissue-specific imprinting of the Gs gene. Proc Natl Acad Sci USA 95:8715–8720This article has been cited by other articles:
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