Correspondence
GNAS1 Mutations and Progressive Osseous Heteroplasia
N Engl J Med 2002; 346:1669-1671May 23, 2002
- Article
To the Editor:
In their article in the January 10 issue, Shore et al. report that they identified heterozygous inactivating GNAS1 mutations in 13 of 18 probands in six families with progressive osseous heteroplasia (POH).1 The defective allele in their cohort was inherited exclusively from the fathers, which led the authors to conclude that paternally inherited inactivating GNAS1 mutations cause POH. Mutations in GNAS1 may lead to a variable phenotype, and retrospective analyses provide evidence that hormone resistance is more likely to occur when the genetic defect is maternally inherited, as Jüppner points out in an accompanying editorial.2
However, we would caution against a premature conclusion that POH may require paternal inheritance of a GNAS1 mutation, on the basis of our GNAS1 mutational analysis of an affected family, which revealed the relatively common 4-bp deletion at codon 189–190 of exon 7 in a brother and a sister and in their mother but not in their father.3 Aside from brachymetacarpia and short stature, the mother did not have features of Albright's hereditary osteodystrophy (AHO). The daughter had typical features of AHO and hormone resistance (pseudohypoparathyroidism type 1a); in contrast, her brother presented in the first year of life with ossification of subcutaneous tissue that was followed by progressive, generalized heterotopic ossification of skeletal muscle, without any clear evidence of hormone resistance. These cases exemplify the enormous phenotypic heterogeneity in persons with mutations in GNAS1, even within one family.
3 ReferencesS. Faisal Ahmed, M.D., M.R.C.P.C.H.
Royal Hospital for Sick Children, Glasgow G3 8SJ, United Kingdom
gcl328@clinmed.gla. ac. uk David G.D. Barr, M.B., F.R.C.P.C.H.
Royal Hospital for Sick Children, Edinburgh EH9 1LF, United KingdomDavid T. Bonthron, F.R.C.P., F.R.C.Path.
St. James's University Hospital, Leeds LS9 7TF, United Kingdom1
Shore EM ,Ahn J ,Jan de Beur S , et al. Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. N Engl J Med 2002;346:99-106
Full Text | Web of Science | Medline2
Juppner H . The genetic basis of progressive osseous heteroplasia. N Engl J Med 2002;346:128-130
Full Text | Web of Science | Medline3
Ahmed SF ,Dixon PH ,Bonthron DT , et al. GNAS1 mutational analysis in pseudohypoparathyroidism. Clin Endocrinol (Oxf) 1998;49:525-531
CrossRef | Web of Science | Medline
To the Editor:
Shore et al. report that patients with POH have inactivating mutations in the GNAS1 gene that are thought to encode a truncated and biologically deficient alpha subunit of the stimulatory G protein (Gsα).1 It is important to know whether Gsα activity was decreased in the affected subjects.
In addition, the distinction between POH and pseudopseudohypoparathyroidism is crucial. In each of the familial cases that has been reported previously (Families 3, 5, and 18 in the report by Shore et al.2), the proband was severely affected by POH, whereas her siblings had relatively minor dermal or subdermal ossifications. In Family 18, affected third-generation members had a similar, mild disorder. In the original report on this family, the proband was described as having classic POH, and all the other affected members in the second and third generation were considered to have the same milder disorder.3 Yet in the current report, Shore et al. state that affected members of the third generation in Family 18 had AHO.2
An alternative hypothesis with regard to the molecular pathogenesis of POH is that patients with mild manifestations of the disorder have pseudopseudohypoparathyroidism and that POH is caused by an additional genetic abnormality.
3 ReferencesZvi Farfel, M.D.
Sheba Medical Center, Tel Hashomer 52621, Israel
farfel@ccsg.tau. ac. il 1
Farfel Z ,Bourne HR ,Iiri T . The expanding spectrum of G protein diseases. N Engl J Med 1999;340:1012-1020
Full Text | Web of Science | Medline2
Shore EM ,Ahn J ,Jan de Beur S , et al. Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. N Engl J Med 2002;346:99-106
Full Text | Web of Science | Medline3
Gardner RJM ,Yun K ,Craw SM . Familial ectopic ossification. J Med Genet 1988;25:113-117
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Our data are consistent with those from previous studies in humans and transgenic mice showing that maternal and paternal transmission of identical GNAS1 mutations causes distinct phenotypes and implicating genomic imprinting as an explanation.1-3
Ahmed et al. describe a patient who had POH-like ectopic ossification and a maternally inherited GNAS1 mutation without hormone resistance, presenting two contradictions of current thought: that maternally inherited mutations are associated with hormone resistance and that paternally inherited mutations are associated with POH.
This person may have had subclinical hormone resistance1 and thus pseudohypoparathyroidism type 1a rather than pseudopseudohypoparathyroidism or POH. It is also possible that in Family 18 in our study, third-generation members with AHO had subclinical hormone resistance. In addition, although extensive, progressive ossification is unusual in AHO, two patients with features of both AHO and POH (apparently through maternal inheritance in one patient) have been described.4
We believe haploinsufficiency for GNAS1 is a necessary, but perhaps not sufficient, cause of POH. If the only requirement for POH were haploinsufficiency, then POH would develop in all patients with GNAS1 mutations, whether they were inherited maternally or paternally. It is also intriguing to consider why extensive ectopic ossification does not develop in all patients with AHO (which can be inherited from either parent3). The phenotypic switching among the generations in Family 18 supports an influence of parental inheritance.
POH and pseudopseudohypoparathyroidism are clinically distinct disorders, although both have been observed to be paternally inherited, with extensive ectopic ossification providing an ascertainment bias for POH. However, these conditions may be more similar than different on a molecular level, representing variable expression.
Dr. Farfel suggests an attractive possibility — that a second genetic mutation distinguishes POH from pseudopseudohypoparathyroidism. The distribution of ectopic ossifications in AHO and POH is reminiscent of the mosaic patterns that characterize inherited disorders dependent on a second mutation for tumor development. Although the normal GNAS1 allele is a candidate for a second mutation, we have been unable to document mutation of the normal GNAS1 allele in samples of ectopic ossification from these patients. Variable expression could also be due to other genetic loci, epigenetic modifications, or environmental factors.3
Mutant GNAS1 messenger RNA is not stably synthesized in most patients with POH, suggesting that a truncated protein is not synthesized — a result consistent with our preliminary data showing reduced levels of Gsα protein. Gsα activity is under investigation, as is the expression of imprinted non–Gsα-encoding transcripts from GNAS1.
4 ReferencesEileen M. Shore, Ph.D.
Frederick S. Kaplan, M.D.
University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6081
shore@mail.med. upenn. edu Michael A. Levine, M.D.
Johns Hopkins University School of Medicine, Baltimore, MD 212871
Jan de Beur SM, Levine MA. Pseudohypoparathyroidism: clinical, biochemical, and molecular features. In: Bilezikian JP, ed. The parathyroids: basic and clinical concepts. 2nd ed. San Diego, Calif.: Academic Press, 2001:807-25.
2
Farfel Z ,Bourne HR ,Iiri T . The expanding spectrum of G protein diseases. N Engl J Med 1999;340:1012-1020
Full Text | Web of Science | Medline3
Juppner H . The genetic basis of progressive osseous heteroplasia. N Engl J Med 2002;346:128-130
Full Text | Web of Science | Medline4
Eddy MC ,De Beur SM ,Yandow SM , et al. Deficiency of the α-subunit of the stimulatory G protein and severe extraskeletal ossification. J Bone Miner Res 2000;15:2074-2083
CrossRef | Web of Science | Medline
Author/Editor Response
The editorialist and a colleague reply:
To the Editor: Ahmed et al. point to a previously described patient in whom maternal inheritance of a relatively common GNAS1 mutation was associated with POH but not with detectable hormone resistance or other features of AHO.1 They suggest that, contrary to the conclusions of Shore et al.,2 POH may not necessarily require paternal inheritance of a GNAS1 mutation. However, on the basis of findings in kindreds with two forms of pseudohypoparathyroidism, type 1a and type 1b, hormone resistance may have a delayed onset or may not become detectable at all in some persons. Pseudohypoparathyroidism type 1b is characterized by renal parathyroid hormone resistance in the absence of AHO and typically in the absence of resistance to other hormones. Unlike pseudohypoparathyroidism type 1a, pseudopseudohypoparathyroidism, and POH, which are all caused by heterozygous GNAS1 mutations affecting the Gsα-encoding exons, the autosomal dominant form of pseudohypoparathyroidism type 1b is presumably caused by regulatory GNAS1 mutations.3,4 On maternal transmission, these mutations are associated with a specific methylation defect within GNAS1 and are thought to eliminate maternal Gsα expression in the renal cortex. As a result of paternal silencing of Gsα transcription in this tissue, Gsα protein levels are likely to be eliminated or considerably diminished, leading to renal parathyroid hormone resistance. In nine families with pseudohypoparathyroidism type 1b that had evidence of (or did not have evidence against) linkage to the GNAS1 locus, 26 patients received a diagnosis between the ages of 3 and 52 years.3,4 Furthermore, a female member of one of these families (D-II/23) had no evidence of parathyroid hormone resistance, although she has two mildly affected children (D-III/34 and D-III/35) and a severely affected brother (D-II/22).3 Similarly, in two recently described siblings with pseudohypoparathyroidism type 1a (Patients 14c and 14d), who carried the same maternally inherited 4-bp deletion at codon 189–190 as the patient described by Ahmed et al.,1 there was considerable variation in the AHO phenotype and in the degree of resistance to parathyroid hormone.5 Like some patients who have either pseudohypoparathyroidism type 1a or pseudohypoparathyroidism type 1b, the patient described by Ahmed et al.1 may have resistance to parathyroid hormone later in life or not at all. Given that this patient's sister and mother have pseudohypoparathyroidism type 1a and pseudopseudohypoparathyroidism (the latter indicated by the presence of brachymetacarpia and short stature and the absence of hormonal resistance), respectively, POH resulting from maternally inherited GNAS1 mutations may represent an incomplete form of pseudohypoparathyroidism type 1a. The underlying mechanism for this form of POH may be distinct from that described by Shore et al., which appears to result only from paternally inherited GNAS1 mutations.2
5 ReferencesMurat Bastepe, M.D., Ph.D.
Harald Jüppner, M.D.
Massachusetts General Hospital, Boston, MA 02114
jueppner@helix.mgh. harvard. edu 1
Ahmed SF ,Dixon PH ,Bonthron DT , et al. GNAS1 mutational analysis in pseudohypoparathyroidism. Clin Endocrinol (Oxf) 1998;49:525-531
CrossRef | Web of Science | Medline2
Shore EM ,Ahn J ,Jan de Beur S , et al. Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. N Engl J Med 2002;346:99-106
Full Text | Web of Science | Medline3
Juppner 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 U S A 1998;95:11798-11803
CrossRef | Web of Science | Medline4
Bastepe M ,Pincus JE ,Sugimoto T , et al. 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
CrossRef | Web of Science | Medline5
Linglart A ,Carel JC ,Garabedian M ,Le T ,Mallet E ,Kottler ML . GNAS1 lesions in pseudohypoparathyroidism Ia and Ic: genotype phenotype relationship and evidence of the maternal transmission of the hormonal resistance. J Clin Endocrinol Metab 2002;87:189-197
CrossRef | Web of Science | Medline
- Citing Articles (6)
Citing Articles
1
Murat Bastepe, Harald Jüppner, Rajesh V. Thakker. 2012. Parathyroid Disorders. , 557-588.
CrossRef2
Kenji Kumagai, Katsuaki Motomura, Masayuki Egashira, Masato Tomita, Masahiko Suzuki, Masataka Uetani, Hiroyuki Shindo. (2008) A case of progressive osseous heteroplasia: a first case in Japan. Skeletal Radiology 37:6, 563-567
CrossRef3
Inessa M. Gelfand, Rachel S. Hub, Eileen M. Shore, Frederick S. Kaplan, Linda A. DiMeglio. (2007) Progressive osseous heteroplasia-like heterotopic ossification in a male infant with pseudohypoparathyroidism type Ia: A case report. Bone 40:5, 1425-1428
CrossRef4
M. Bastepe. (2005) Pseudohypoparathyroidism, Gs , and the GNAS Locus. International Bone and Mineral Society Knowledge Environment 2:12, 20-32
CrossRef5
Murat Bastepe, Harald Jüppner. (2005) <i>GNAS</i> Locus and Pseudohypoparathyroidism. Hormone Research 63:2, 65-74
CrossRef6
David Haig. (2004) GENOMIC IMPRINTING AND KINSHIP: How Good is the Evidence?. Annual Review of Genetics 38:1, 553-585
CrossRef
