JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome

X-linked autoimmunity-allergic disregulation syndrome (XLAAD) is an X-linked recessive immunological disorder characterized by multisystem autoimmunity, particularly early-onset type 1 diabetes mellitus, associated with manifestations of severe atopy including eczema, food allergy, and eosinophilic...

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Bibliographic Details
Published in:The Journal of clinical investigation 2000-12, Vol.106 (12), p.R75-R81
Main Authors: Chatila, T A, Blaeser, F, Ho, N, Lederman, H M, Voulgaropoulos, C, Helms, C, Bowcock, A M
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Autoimmune Diseases - genetics
Autoimmune Diseases - immunology
Base Sequence
Cell Differentiation
Diabetes Mellitus, Type 1 - genetics
Diabetes Mellitus, Type 1 - immunology
DNA Mutational Analysis
Female
Food Hypersensitivity - genetics
Food Hypersensitivity - immunology
Forkhead Transcription Factors
Genetic Linkage - genetics
Haplotypes
Humans
Leucine Zippers
Male
Molecular Sequence Data
Mutation - genetics
Nuclear Proteins - chemistry
Nuclear Proteins - genetics
Nuclear Proteins - immunology
Pedigree
Protein Structure, Tertiary
Rapid Publication
RNA Splice Sites - genetics
Sequence Alignment
Sequence Homology, Amino Acid
Syndrome
Th2 Cells - cytology
Th2 Cells - immunology
Transcription Factors - chemistry
Transcription Factors - genetics
Transcription Factors - immunology
X Chromosome - genetics
X Chromosome - immunology
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Summary:X-linked autoimmunity-allergic disregulation syndrome (XLAAD) is an X-linked recessive immunological disorder characterized by multisystem autoimmunity, particularly early-onset type 1 diabetes mellitus, associated with manifestations of severe atopy including eczema, food allergy, and eosinophilic inflammation. Consistent with the allergic phenotype, analysis of two kindreds with XLAAD revealed marked skewing of patient T lymphocytes toward the Th2 phenotype. Using a positional-candidate approach, we have identified in both kindreds mutations in JM2, a gene on Xp11.23 that encodes a fork head domain-containing protein. One point mutation at a splice junction site results in transcripts that encode a truncated protein lacking the fork head homology domain. The other mutation involves an in-frame, 3-bp deletion that is predicted to impair the function of a leucine zipper dimerization domain. Our results point to a critical role for JM2 in self tolerance and Th cell differentiation.
ISSN:0021-9738
DOI:10.1172/jci11679