Ancestral Founder Mutation of the <i>Nude</i> (<i>FOXN1</i>) Gene in Congenital Severe Combined Immunodeficiency Associated with Alopecia in Southern Italy Population

TLDR

FOXN1 mutations, notably the R255X nonsense variant, cause a Nude/SCID phenotype and were first identified in a small southern Italian community where affected children died early; an ancestral couple from the 19th century is linked to this mutation. The study screened 30 % of the village population for the R255X FOXN1 mutation. The authors screened 843 inhabitants and genotyped microsatellite markers D17S2187 and D17S1880 flanking FOXN1 to confirm a single ancestral origin. The screening identified 55 heterozygous carriers (6.52 %) among 843 residents, linked to 39 families in a 7‑generation pedigree of 483 individuals, with three consistent haplotypes supporting a single ancestral origin.

Abstract

Summary Genetic alterations of the FOXN1 transcription factor, selectively expressed in thymic epithelia and skin, are responsible in both mice and humans for the Nude/SCID phenotype. The first described human FOXN1 mutation was a C792T transition in exon 5 resulting in the nonsense mutation R255X, and was detected in two probands originated from a small community in southern Italy. In this community, four additional children affected with congenital alopecia died in early childhood because of severe infections. In this study, we report on the screening for this mutation in 30% of the village population. This analysis led us to identify 55 heterozygous carriers (6.52%) of the R255X mutation out of 843 inhabitants screened. A genealogical study revealed that these subjects, belonging to 39 families, were linked in an extended 7‐generational pedigree comprising 483 individuals. Through the archival database a single ancestral couple, born at the beginning of the 19th century, was identified. To confirm the ancestral origin of the mutation we genotyped two microsatellite markers, D17S2187 and D17S1880, flanking the FOXN1 gene on chromosome 17. The three haplotypes identified, 3/R255X/3, 3/R255X/2 and 3/R255X/1, are consistent with a single ancestral origin for the mutation R255X.