title: A novel mutation of the autoimmune regulator gene in an Italian kindred with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, acting in a dominant fashion and strongly cosegregating with hypothyroid autoimmune thyroiditis.
abstract: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is a rare autosomal recessive disorder characterized by hypoparathyroidism, adrenal failure, chronic mucocutaneous candidiasis, and ectodermal dystrophies and other organ-specific autoimmune diseases. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is caused by mutations of the autoimmune regulator gene. We identified an Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy and a pattern of inheritance suggestive of a dominant mechanism. Serological and clinical studies showed a high prevalence of hypothyroid autoimmune thyroiditis in affected members with classical autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Direct sequencing of the entire coding region of the autoimmune regulator gene revealed the presence in the proband of a novel missense (G228W) mutation in exon 6 in a heterozygous state. The same heterozygous mutation was identified in all family members with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy and/or hypothyroid autoimmune thyroiditis. None of the unaffected family members and 50 unrelated Italian controls carried the mutation. In contrast with all other autoimmune regulator mutations reported in families, the novel G228W mutation acts in a dominant fashion in our family, as only one heterozygous mutation was found in the entire coding sequence of the autoimmune regulator gene in the proband. Moreover, analysis of the family tree showed direct transmission of the hypothyroid autoimmune thyroiditis/polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype to the offspring in each generation in the absence of consanguinity, further supporting a dominant inheritance. The G228W closely cosegregated with hypothyroid autoimmune thyroiditis in our family, whereas a low penetrance of the full autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype was observed. In conclusion, we report a novel mutation of the autoimmune regulator gene in a family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, closely cosegregating with hypothyroid autoimmune thyroiditis. The G228W mutation acts in a dominant fashion and may shed light on the structure-function relationship of the autoimmune regulator protein.
authors.affiliation: Dipartimento di Endocrinologia e Metabolismo, Universita' degli Studi di Pisa, Via Paradisa 2, 56124 Pisa, Italy. fcetani@yahoo.it
authors.forename: F
authors.initials: F
authors.lastname: Cetani
authors.forename: G
authors.initials: G
authors.lastname: Barbesino
authors.forename: S
authors.initials: S
authors.lastname: Borsari
authors.forename: E
authors.initials: E
authors.lastname: Pardi
authors.forename: L
authors.initials: L
authors.lastname: Cianferotti
authors.forename: A
authors.initials: A
authors.lastname: Pinchera
authors.forename: C
authors.initials: C
authors.lastname: Marcocci
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005809:Genes, Regulator; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010281:Parathyroid Hormone / Q000097:blood; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D013967:Thyroiditis, Autoimmune / Q000235:genetics*; D013972:Thyrotropin / Q000097:blood; D014157:Transcription Factors / Q000235:genetics*; D000096927:AIRE Protein
chemical_list: D010281:Parathyroid Hormone; D013972:Thyrotropin; D014157:Transcription Factors; D000096927:AIRE Protein