Molecular analysis of a large cohort of patients with the hyper immunoglobulin M (IgM) syndrome.
The hyper immunoglobulin M (IgM) syndrome (HIGM), characterized by recurrent infections, low serum IgG and IgA, normal or elevated IgM, and defective class switch recombination and somatic hypermutation, is a heterogenous disorder with at least 5 distinct molecular defects, including mutations of the genes coding for the CD40 ligand (CD40L) and IKK-gamma (NEMO) genes, both X-linked; and mutations of CD40, activation-induced cytidine deaminase (AICDA), and uracil-DNA glycosylase (UNG), associated with autosomal recessive HIGM syndromes. To investigate the molecular basis of HIGM, we determined the prevalence of mutations affecting these 5 genes in a cohort of 140 patients (130 males and 10 females). Those patients without a molecular diagnosis were subsequently evaluated for mutations of the following genes: inducible CO-stimulator molecule (ICOS), ICOS ligand (ICOSL), and if male, Bruton tyrosine kinase (Btk) and SLAM-associated protein (SAP/SH2D1A). We found mutations of CD40L in 98 males; AICDA in 4 patients (3 males, 1 female); UNG in one adult male; and Btk in 3 boys. Of the remaining 25 males, one infant with hypohidrotic ectodermal dysplasia had a mutation of NEMO. None of the remaining 33 patients (24 males/9 females) had mutations affecting CD40, ICOS, ICOSL, or SH2D1, and are best classified as common variable immune deficiency (CVID), although other genes, including some not yet identified, may be responsible.
Lee
Wen-I
WI
Department of Pediatrics, University of Washington, School of Medicine, Children's Hospital and Regional Medical Center, 307 Westlake Ave N, Suite 300, Seattle, WA 98109, USA.
Torgerson
Troy R
TR
Schumacher
Michael J
MJ
Yel
Leman
L
Zhu
Qili
Q
Ochs
Hans D
HD
D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D019013:CD40 Antigens / Q000235:genetics; D023201:CD40 Ligand / Q000235:genetics; D015331:Cohort Studies; D003564:Cytidine Deaminase; D043525:Cytosine Deaminase / Q000235:genetics; D045647:DNA Glycosylases / Q000235:genetics; D005192:Family Health; D005260:Female; D006801:Humans; D006942:Hypergammaglobulinemia / Q000453:epidemiology / Q000235:genetics*; D051550:I-kappa B Kinase; D007075:Immunoglobulin M; D008297:Male; D017720:Molecular Epidemiology; D009154:Mutation; D015995:Prevalence; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D051981:Uracil-DNA Glycosidase; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D019013:CD40 Antigens; D007075:Immunoglobulin M; D023201:CD40 Ligand; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D045647:DNA Glycosylases; D051981:Uracil-DNA Glycosidase; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D043525:Cytosine Deaminase; D003564:Cytidine Deaminase