Two mutations of the Gsα gene in two Japanese patients with sporadic pseudohypoparathyroidism type Ia

Ishikawa, Yuichi; Tajima, Toshihiro; Nakae, Jun; Nagashima, Tomomi; Satoh, K.; Okuhara, Koji; Fukui, Kenji

doi:10.1007/s100380170062

Cited by 22 publications

(20 citation statements)

References 23 publications

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“…We obtained the approval of the study by the institutional ethical committee of Kansai Medical University and Matsubara Municipal Hospital and the parents gave their written informed consent for DNA analysis. The 13 exons and exon-intron boundaries of the Gsα gene were amplified by polymerase chain reaction (PCR) using oligonucleotide primers as described in a previous report [14]. Direct sequencing from both 5' and 3' ends of the amplified genomic DNA fragments revealed the substitution of histidine for arginine at position 385 (R385H) in exon 13 of the GNAS gene (Fig.…”

Section: A Report Of Casementioning

confidence: 99%

A Pseudohypoparathyroidism Type Ia Patient with Normocalcemia

et al. 2008

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Abstract. Pseudohypoparathyroidism type Ia (PHP-Ia), one of 4 types of PHP, is a genetic disease characterized by clinical hypoparathyroidism caused by parathyroid hormone (PTH) resistance. In addition, patients with PHP-Ia show resistance to other hormones as well as Albright's hereditary osteodystrophy (AHO), a constellation of features including short stature, obesity, brachydactyly, ectopic ossifications, and/or mental retardation. Hypocalcemia is one of the hallmarks of PHP-Ia, but several PHP-Ia patients have been described to have normocalcemia. We encountered a 10-yearold girl with typical Albright's hereditary osteodystrophy with round face, short stature, brachydactyly, and obesity. Biochemical examination showed normocalcemia and increased PTH levels. Ellsworth-Howard test did not show any responses of urinary cAMP and phosphate. Based on these findings, she was diagnosed as having PHP-Ia with normocalcemia. Sequencing analysis of the GNAS gene identified a heterozygous missense mutation in exon 13 (R385H), which was previously reported in a PHP-Ia patient. The exact reason for her normocalcemia is not determined, but we must recognize heterogeneous biochemical findings even in PHP-Ia.

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Section: A Report Of Casementioning

confidence: 99%

A Pseudohypoparathyroidism Type Ia Patient with Normocalcemia

et al. 2008

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“…1B) was missed until recently. The R231H mutation in exon 9 of GNAS, reported in previous PHP1a patients [Farfel et al, 1996;Ishikawa et al, 2001], was identified in this family. Both sons are full heterozygotes and the mother shows somatic mosaicism.…”

Section: Introductionmentioning

confidence: 76%

“…Designations of patients are identical to that used in original case reports [Farfel et al, 1996;Ishikawa et al, 2001].…”

Section: Methodsmentioning

confidence: 99%

Pseudohypoparathyroidism type 1a and the GNAS p.R231H mutation: Somatic mosaicism in a mother with two affected sons

Ngai

Chijiwa

Mercimek-Mahmutoglu

et al. 2010

American J of Med Genetics Pt A

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Pseudohypoparathyrodism (PHP) is a disorder caused by mutations in the guanine nucleotide-binding α-subunit (GNAS). We sought to determine the genetic origin of PHP1a in one affected family. We identified the previously reported Gsα R231H mutation in family members affected with PHP1a. DNA analysis found that the two clinically affected sons are heterozygous for the mutation. The sons have PHP1a, manifesting obesity, intellectual disability, hypogonadism, hypothyroidism and elevated PTH levels. Initial DNA sequencing did not detect the mutation in either parent. However, their mother displayed some features of PHP, including elevated PTH levels and asymmetrical metacarpal shortening. Using molecular cloning, we detected the mutation at low levels in the mother's leukocyte DNA, consistent with somatic mosaicism and her mildly affected status. Thus, we have identified additional cases of PHP1a caused by the Gsα R231H mutation. In this family, the mother has a milder phenotype due in part to somatic mosaicism, whereas the two affected sons have full PHP1a. Though somatic mosaicism for activating GNAS mutations is known to occur in McCune-Albright syndrome, this is the first report confirming somatic mosaicism for a hypofunctioning GNAS mutation in a PHP kindred.

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“…Of the 13 patients who were reported to have elevated serum TSH concentrations (10, 11, 13 -15, 17 -19, 22, 23) eight were treated with thyroid hormone (10,13,15,17,19). Four had low thyroid hormone levels (10,13,14,17), whereas in four other individuals the levels were normal (11,15,22,23). In the remaining five cases thyroid hormone levels were not mentioned (18,19).…”

Section: Discussionmentioning

confidence: 99%

A new heterozygous mutation (L338N) in the human Gsalpha (GNAS1) gene as a cause for congenital hypothyroidism in Albright's hereditary osteodystrophy

Pohlenz

Ahrens

Hiort

2003

European Journal of Endocrinology

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Objective: To identify the molecular defect by which psychomotor retardation is caused in two brothers with congenital hypothyroidism who received adequate treatment with L-thyroxine. Case report: A six-year-old boy presented with psychomotor retardation and congenital primary hypothyroidism (CH). The patient had a normal blood thyrotrophin (TSH) level on neonatal screening, but low total serum thyroxine and triiodothyronine concentrations prompting thyroid hormone substitution shortly after birth. Nevertheless, psychomotor development was retarded and the patient underwent further investigation. Typical features of Albright's hereditary osteodystrophy (AHO) such as round face, obesity, and shortened 1st, 4th and 5th metacarpals were found. Methods and results: Further investigation confirmed AHO with pseudohypoparathyroidism (PHP) type Ia. The boy had a mild resistance to parathyroid hormone and a reduced adenylyl cyclase stimulating protein (Gsa) activity in erythrocytes. DNA analysis detected a new heterozygous mutation (L338N) in the Gsa protein (GNAS1) gene. This mutation was also present in the patient's brother who had similar features and was also treated with thyroid hormone because of CH, and in the phenotypically normal-looking mother who had a normal calcium metabolism but a reduced Gsa protein activity in erythrocytes suggestive of pseudopseudohypoparathyroidism. Conclusion: In patients with CH, in whom the neurological outcome is poor even under adequate thyroid hormone substitution, PHP Ia may be suspected, especially when symptoms of AHO are present.

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Two mutations of the Gsα gene in two Japanese patients with sporadic pseudohypoparathyroidism type Ia

Cited by 22 publications

References 23 publications

A Pseudohypoparathyroidism Type Ia Patient with Normocalcemia

A Pseudohypoparathyroidism Type Ia Patient with Normocalcemia

Pseudohypoparathyroidism type 1a and the GNAS p.R231H mutation: Somatic mosaicism in a mother with two affected sons

A new heterozygous mutation (L338N) in the human Gsalpha (GNAS1) gene as a cause for congenital hypothyroidism in Albright's hereditary osteodystrophy

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