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 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.
Chatila
T A
TA
Department of Pediatrics, and. Department of Pathology and Immunology and the Center for Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA. chatila@kids.wustl.edu
Blaeser
F
F
Ho
N
N
Lederman
H M
HM
Voulgaropoulos
C
C
Helms
C
C
Bowcock
A M
AM
D000595:Amino Acid Sequence; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D001483:Base Sequence; D002454:Cell Differentiation; D004252:DNA Mutational Analysis; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D005512:Food Hypersensitivity / Q000235:genetics* / Q000276:immunology; D051858:Forkhead Transcription Factors; D008040:Genetic Linkage / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D016350:Leucine Zippers; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D010375:Pedigree; D017434:Protein Structure, Tertiary; D022821:RNA Splice Sites / Q000235:genetics; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013577:Syndrome; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D014960:X Chromosome / Q000235:genetics* / Q000276:immunology
D051858:Forkhead Transcription Factors; D009687:Nuclear Proteins; D022821:RNA Splice Sites; D014157:Transcription Factors