title: Molecular analysis of a large cohort of patients with the hyper immunoglobulin M (IgM) syndrome.
abstract: 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.
authors.affiliation: 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.
authors.forename: Wen-I
authors.initials: WI
authors.lastname: Lee
authors.forename: Troy R
authors.initials: TR
authors.lastname: Torgerson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Schumacher
authors.forename: Leman
authors.initials: L
authors.lastname: Yel
authors.forename: Qili
authors.initials: Q
authors.lastname: Zhu
authors.forename: Hans D
authors.initials: HD
authors.lastname: Ochs
mesh_terms: 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)
chemical_list: 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