A novel GNAS-Gsα splice donor site variant in a girl with pseudohypoparathyroidism type 1A and her mother with pseudopseudohypoparathyroidism.

IF 1 Q4 ENDOCRINOLOGY & METABOLISM

Clinical Pediatric Endocrinology Pub Date : 2024-01-01 Epub Date: 2024-01-06 DOI:10.1297/cpe.2023-0065

Shinichiro Sano, Shotaro Iwamoto, Rie Matsushita, Yohei Masunaga, Yasuko Fujisawa, Tsutomu Ogata

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Abstract

We encountered a Chinese girl with pseudohypoparathyroidism type 1A (PHP1A) and her mother with pseudopseudohypoparathyroidism (PPHP). Sequencing analysis of GNAS-Gsα revealed a heterozygous c.212+2T>C variant (NM_000516.4) affecting the canonical splice donor site of intron 2 in the girl and her mother. RT-PCR performed on mRNA samples obtained from cycloheximide-treated and cycloheximide-untreated lymphoblastoid cell lines of this girl revealed the utilization of an alternative splice donor site at 33-34 bp from the boundary between exon 2 and intron 2 and the production of an aberrant mRNA with a retention of a 32 bp intronic sequence between exon 2 and exon 3 (p.(Gly72Lysfs*39)), which satisfied the condition for the occurrence of nonsense-mediated mRNA decay, as predicted by SpliceAI. This study revealed the molecular consequences of disruption of the canonical splice donor site and confirmed the clinical utility of SpliceAI.

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一名患有假性甲状旁腺功能亢进症1A型的女孩及其患有假性甲状旁腺功能亢进症的母亲的新型GNAS-Gsα剪接供体位点变异。

我们发现一名中国女孩患有假性甲状旁腺功能减退症1A型（PHP1A），其母亲患有假性甲状旁腺功能减退症（PPHP）。GNAS-Gsα的测序分析表明，该女孩及其母亲体内存在一个影响内含子2的规范剪接供体位点的杂合c.212+2T>C变异（NM_000516.4）。对该女孩经环己亚胺处理和未经环己亚胺处理的淋巴母细胞系中获得的 mRNA 样本进行 RT-PCR 检测发现，在外显子 2 和内含子 2 之间的 33-34 bp 处使用了一个替代剪接供体位点，并产生了一个异常 mRNA，在外显子 2 和外显子 3 之间保留了 32 bp 的内含子序列（p.212+2T>C）。(Gly72Lysfs*39），这符合 SpliceAI 预测的发生无义介导的 mRNA 衰减的条件。这项研究揭示了破坏典型剪接供体位点的分子后果，并证实了 SpliceAI 的临床实用性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical Pediatric Endocrinology ENDOCRINOLOGY & METABOLISM-

CiteScore

2.40

自引率

7.10%

发文量