ClinVar Genomic variation as it relates to human health

Alopecia (present) , Failure to thrive (present) , Sparse hair (present) , Alopecia of scalp (present) , Coarse hair (present) , Exotropia (present) , Delayed skeletal maturation (present) , Developmental cataract (present) (less)

In a Chinese mother and daughter (family 2) with follicular ichthyosis, atrichia, and photophobia (IFAP2; 619016), Wang et al. (2020) identified heterozygosity for a c.1579C-T transition (c.1579C-T, NM_004176.3) in the SREBF1 gene, resulting in an arg527-to-cys (R527C) substitution at a highly conserved residue within a motif crucial for S1P recognition and cleavage. The R527C mutation was also detected in 8 unrelated IFAP patients of varying ethnicities, including Chinese, German, Congolese, Italian, African American, and Indian. The variant, which was not found in the ExAC or gnomAD databases, was confirmed to have arisen de novo in 4 of the sporadic cases. Nuclear extracts from transiently transfected HEK293 cells expressing the R527C mutant under sterol-free conditions did not show the 71-kD band corresponding to the transcriptionally active cleaved form of SREBF1 that was seen in cells expressing wildtype SREBF1. Immunostained transfected cells showed the most pronounced signal in the nuclei of wildtype cells, whereas nuclear staining was barely discernable in cells expressing the R527C mutant; in the latter cells, signal was largely restricted to the cytoplasm, suggesting that the mutant failed to translocate to the nucleus. In addition, the R527C mutant showed significantly reduced transcriptional activity, to only 33% of wildtype activity. RNA sequencing of scalp skin from the affected mother and daughter in family 2 revealed a dramatic reduction in transcript levels of LDLR (606945) and of keratin genes known to be expressed in the outer root sheath of hair follicles. Scalp keratinocytes also showed an increased rate of apoptosis, which the authors suggested might contribute to skin hyperkeratosis and hypotrichosis. (less)

In a 19-year-old woman (P1) and an unrelated 20-year-old woman (P2) with hereditary mucoepithelial dysplasia (HMD; 158310), Morice-Picard et al. (2020) identified heterozygosity for a c.1669C-T transition (c.1669C-T, NM_001005291.2) in exon 9 of the SREBF1 gene, resulting in an arg557-to-cys (R557C) substitution at a highly conserved residue, essential for cleavage, within the luminal loop. The mutation was discrepantly noted as occurring in exon 18 in Figure 2 of the report. The unaffected parents of P1 did not carry the mutation, indicating that it arose de novo in the proband, and the R557C variant was also not found in the dbSNP, 1000 Genomes Project, or gnomAD databases. In a Mexican father and daughter with HMD, Chacon-Camacho et al. (2020) identified heterozygosity for the R557C mutation in the SREBF1 gene. (less)