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

Abstract

Nuclear factor one A (NFIA) is a transcription factor that regulates the development of the central nervous system. Haploinsufficiency of the NFIA gene causes NFIArelated 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 À/À 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 À/À 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.

Tcte1knockout influence on energy chain transportation, apoptosis and spermatogenesis – implications for male infertility

“…: P1/P2 protamines, Pde8b , Trim28 , Tcfl5 ), and to the other diseases (i.e. : PIKFYVE in cataract, NFIA , SCN1A in neurological or epilepsy disturbances, KLF1 in hemoglobin persistenece, NR5A2 in pancreatic cancer), seem to confirm that the severity of the phenotype depends on the gene expression level [Jodar and Oliva, 2014; Mei et al, 2022; Ogura et al, 2022; Heshusius et al, 2022; Valassina et al, 2022; Sandhu et al, 2021; Leal et al, 2021; Tan et al, 2020; Xu et al, 2022]. We have documented variable phenotypes for a novel TCTE1 variant c.374T>G (p.Ile125Arg) that has been documented in seven males, including: azoospermia, crypto-, and severe oligoasthenozoospermics.…”

Significant phenotypic variability in a multigenerational family with an NFIA missense mutation: Case series and review of the literature

“…2 Deletion of NFIA often occurs as part of a multigenic microdeletion, although 20 cases resulting from smaller intragenic deletions or point mutations have been reported. [3][4][5][6][7][8][9][10] Clinical manifestations of NFIA-related disorder are highly variable, but almost always include abnormalities, such as hypoplasia, of the corpus callosum. Macrocephaly and nonspecific but distinct facial features have also been reported.…”

“…The general mechanism of disease is haploinsufficiency of a single NFIA allele, although missense mutations have been reported. 2,3,[5][6][7] The prognosis of NFIA-related disorder is not well known. This disorder is likely underdiagnosed and underreported, making it difficult to determine if life span is affected.…”

“…Truncation or deletion of NFIA causing haploinsufficiency can result in an NFIA ‐related disorder 2 . Deletion of NFIA often occurs as part of a multigenic microdeletion, although 20 cases resulting from smaller intragenic deletions or point mutations have been reported 3–10 …”

“…Mutations in NFIA are often sporadic, but they can be inherited in an autosomal dominant pattern. The general mechanism of disease is haploinsufficiency of a single NFIA allele, although missense mutations have been reported 2,3,5–7 …”