The p.Thr395Met missense variant of NFIA found in a patient with intellectual disability is a defective variant

Yurie Ogura, Tomoko Uehara, Kota Ujibe, Hiroshi Yoshihashi, Mamiko Yamada, Hisato Suzuki, Toshiki Takenouchi, Kenjiro Kosaki, Hiromi Hirata

研究成果: Article査読

抄録

Nuclear factor one A (NFIA) is a transcription factor that regulates the development of the central nervous system. Haploinsufficiency of the NFIA gene causes NFIA-related disorder, which includes brain abnormalities and intellectual disability, with or without urinary tract defects. Intragenic deletions, nonsense variants, frameshift variants, and missense variants in one allele of the NFIA gene have been reported to cause various neurological and urogenital symptoms. Here we report a 10-year-old male patient with developmental delay, coarctation of the aorta, and distinctive facial features. Exome analysis identified a rare de novo heterozygous missense variant p.Thr395Met in NFIA. We employed zebrafish as a model organism in our NFIA analysis and found that nfia−/− zebrafish initially showed a loss of commissural axons in the brain, and eventually underwent growth retardation resulting in premature death. Impairment of the commissural neurons in nfia−/− zebrafish embryos could be restored by the expression of wild-type human NFIA protein, but not of mutant human protein harboring the p.Thr395Met substitution, indicating that this variant affects the function of NFIA protein. Taken together, we suggest that the p.Thr395Met allele in the NFIA gene is relevant to the pathogenesis of NFIA-related disorder.

本文言語English
ページ(範囲)1184-1192
ページ数9
ジャーナルAmerican Journal of Medical Genetics, Part A
188
4
DOI
出版ステータスPublished - 2022 4月

ASJC Scopus subject areas

  • 遺伝学
  • 遺伝学(臨床)

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