Bi‐allelic recessive loss‐of‐function mutations in FIGLA cause premature ovarian insufficiency with short stature

作者：Ping Yuan, Zuyong He, Silong Sun, Yu Li, Wenjun Wang, Xinyu Liang, Xuefeng Xie, Yiqi Jiang, Dongzi Yang · 发表于：Clinical Genetics · 年份：2018 · DOI：10.1111/cge.13486 · 被引用次数：17 · 研究领域：Reproductive Biology and Fertility、Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities、Growth Hormone and Insulin-like Growth Factors

Premature ovarian insufficiency (POI) is a group of heterogeneous disorders characterized by decreased ovarian reserve and increased follicle stimulating hormone (FSH) levels. It is rarely associated with short stature. FIGLA mutations with POI are identified with regard to heterozygosity; till date, only one affected family has been identified with homozygous mutations in FIGLA but without functional evaluation. Here, we described two POI patients from a consanguineous family from China. An 18-year-old girl and her sister presented with primary amenorrhea and increased FSH and luteinizing hormone levels, but the sister also presented with short stature and bone age delay. Whole-genome sequencing analysis identified a recurrent homozygous mutation in the FIGLA gene, c.2 T > C (p.Met1Thr), in this family member with POI; this variant was segregated within the pedigree. This change was absent in 382 control subjects, and we did not detect any mutations in 39 other idiopathic POI patients. in vitro functional analysis indicates that the p.Met1Thr mutation does not affect the transcription of the FIGLA gene, but blocks the synthesis of the full-length FIGLA protein. Our results support the notion that bi-allelic recessive loss-of-function effects of FIGLA contribute to POI patients with short stature and expand the FIGLA-related phenotypic spectrum.