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

Abstract

SummaryGenetic 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.

FOXN1 Deficiency: from the Discovery to Novel Therapeutic Approaches

“…The identification of the full equivalent human phenotype of nude mouse occurred surprisingly about 30 years later with the description of two Italian sisters, who presented congenital alopecia, eyebrows, eyelashes, and nail dystrophy associated with a severe T cell immunodeficiency, as detailed below [2]. The consanguinity of the parents and the small community where the patients originated from suggested an autosomal recessive inheritance [18]. The time gap from the original mouse description led to hypothesize a lethal phenotype in subjects with complete expression.…”

“…In the small community of south Italy, where the first two sisters with FOXN1 deficiency where identified, additional cases of patients with congenital alopecia and early child death because of severe infections were reported [18]. Interestingly, 55 subjects of 843 inhabitants studied were found to carry the heterozygous FOXN1 mutation.…”

“…Immunological alterations have also been documented in a heterozygous carrier, including lymphopenia and absence of TREC (personal communication by Dr. Gelfand). Unfortunately, no lymphocyte counts or other lab investigations were performed in the large group of heterozygous subjects of south Italy [18].…”

Overexpression of Foxn1 attenuates age-associated thymic involution and prevents the expansion of peripheral CD4 memory T cells

“…4 Functional maturation of TEC requires expression of the transcription factor forkhead box n1 (Foxn1); mutations in both mouse Foxn1 and human FOXN1 genes result in athymic and hairless conditions as seen in nude mice and patient with severe combined immunodeficiency syndrome. 5,6 We previously showed that the decline in the expression of Foxn1 in thymic stroma correlates with the onset of reduction in thymocyte numbers and production of naive T cells as determined by the total number of signal joint TCR excised circle (sjTREC) in the thymus, suggesting that Foxn1 may play a role in age-associated thymic involution. 3 Subsequent work by others demonstrated a role of Foxn1 in the cross-talk between TEC and developing thymocytes, which is required for thymopoiesis.…”

Ethylnitrosourea‐induced thymus‐defective mutants identify roles ofKIAA1440, TRRAP, andSKIV2L2in teleost organ development

“…Most cases of the DiGeorge syndrome are a result of the deletion of chromosome 22q11.2, and tbx1 encoded in this region is responsible for the onset of defective thymus development in many DiGeorge syndrome patients [9,10]. It was also shown that mutations in foxn1 in human and mouse can induce the nude phenotype that is characterized by defective thymus development and hairless caused by defective hair follicles (OMIM 601705) [11,12]. Defects in functional thymus development may sometimes result in autoimmune diseases.…”