JM2, encoding a fork head–related protein, is mutated in X-linked autoimmunity–allergic disregulation syndrome
Talal A. Chatila, Frank Blaeser, Nga Ho, Howard M. Lederman, Constantine Voulgaropoulos, Cindy Helms, Anne M. Bowcock
Talal A. Chatila, Frank Blaeser, Nga Ho, Howard M. Lederman, Constantine Voulgaropoulos, Cindy Helms, Anne M. Bowcock
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JM2, encoding a fork head–related protein, is mutated in X-linked autoimmunity–allergic disregulation syndrome

Abstract

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.

Authors

Talal A. Chatila, Frank Blaeser, Nga Ho, Howard M. Lederman, Constantine Voulgaropoulos, Cindy Helms, Anne M. Bowcock

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Identification of a 5′ splice junction mutation in JM2 IVS9 of XLAAD-100...
Identification of a 5′ splice junction mutation in JM2 IVS9 of XLAAD-100 index case. (a) Analysis of JM2 IVS9 5′ splice junction site sequence in the index case and his sibling brother control. An Α→G transition at position +4 of the 5′ splice junction site is noted in the patient sequence (indicated by an arrowhead). (b and c) Exon 9 skipping in XLAAD-100 index case. (b) RT-PCR analysis of JM2 open reading frame 3′ end (bp 639–1036) in patient and control mRNA transcripts, revealing faster migration of patient RT-PCR product on agarose gel electrophoresis as compared with control product. MWM, molecular weight markers. (c) Sequence analysis of RT-PCR products shown in b, confirming the presence of exon 9 deletion and frame shift alteration in patient sequence. (d) Schematic representation of predicted mutant JM2 protein product in XLAAD-100 index case, showing truncation of the protein just before the fork head homology domain.