GNAS基因突变致2例假性甲状旁腺功能减退症Ⅰa型

Two cases of pseudohypoparathyroidism type Ⅰa caused by GNAS gene mutation

目的对2例假性甲状旁腺功能减退症Ⅰa型(pseudohypoparathyroidism typeⅠa,PHP-Ⅰa)患者进行临床特征及GNAS基因分析以提高对此病的认识。方法采集2例PHP-Ⅰa患者及亲属外周血提取DNA后对GNAS基因13个外显子及相邻内含子通过聚合酶链式反应进行扩增,然后进行DNA测序,并选取100名健康对照对新突变位点进行检测。结果病例1为18岁女性,因闭经就诊,具有Albright遗传性骨营养不良症(Albright's hereditary osteodystrophy,AHO)体型及亚临床甲状腺功能减退,但多次查血钙磷均正常。GNAS基因检测发现该患者携带c.715A>G(p.N239D)杂合错义突变,其母也携带该突变,临床表现为假假性甲状旁腺功能减退症(pseudo-pseudohypoparathyroidism,PPHP),该突变曾报道为致病突变。病例2为33岁男性,因反复搐搦就诊,主要表现为AHO体型并低血钙、高血磷、高PTH、亚临床甲状腺功能减退症。GNAS基因检测发现患者及其母携带c.433-2A>G(IVS5-2A>G)杂合剪切突变,该突变位于内含子5的3′端高度保守剪切位点,且在100名健康人群中未检出,人类基因突变数据库(Human Gene Mutation Database,HGMD)未见报道,是新发突变。结论本研究发现1个新的GNAS基因突变,拓宽了对PHP-Ⅰa发病机制的认识。PHP-Ⅰa临床表现多样,易误诊及漏诊,早期识别PHP-Ⅰa相关症状,及早进行GNAS基因筛查有助于本病的诊断及治疗。

Objective In this study,phenotype and GNAS(guanine nucleotide-binding protein alpha-stimulating activity polypeptide 1)gene analysis were performed in two patients with pseudohypoparathyroidism typeⅠa(PHP-Ⅰa).Methods Peripheral blood samples were collected from the two patients with PHP-Ⅰa and their families.All exons of the GNAS gene and adjacent introns were amplified by PCR and subsequently sequenced.Results Case 1 was an 18-year-old female who visited hospital because of amenorrhea,and manifested Albright's osteodystrophy(AHO)and hypothyroidism.But her serum calcium and phosphorus kept normal.A heterozygous c.715A>G(p.N239D)mutation of the GNAS gene was identified in the patient.This mutation was also found in her mother,who was diagnosed with pseudopseudo-hypoparathyroidism(PPHP).Case 2 was a 33-year-old male who exhibited repeated convulsions.He had typical AHO features and decreased serum calcium,elevated phosphorus and PTH.Other hormone tests also showed elevated TSH.A heterozygous mutation of c.433-2A>G(IVS5-2A>G)in intron 5 of the GNAS gene was identified in the patient and his mother.The IVS5-2A>G mutation was not detected in 100 healthy controls.It has not been reported in the HGMD database and is a novel mutation.Conclusions We identified a new mutation of GNAS gene,which contributed to better understanding of pathogenesis of PHP-Ⅰa.PHP-Ⅰa shows various clinical features and can be easily misdiagnosed.Early recognition of clinical characteristics and screening for GNAS gene are important for early diagnosis and treatment.