title: Severe combined immunodeficiency associated with nephrogenic diabetes insipidus and a deletion in the Xq28 region.
abstract: We evaluated a baby boy with severe combined immunodeficiency (SCID) and X-linked nephrogenic diabetes insipidus (NDI). This patient had less than 10% CD3+ T cells, almost all of which were positive for CD4 and CD45RO. Genetic studies demonstrated a 34.4 kb deletion at Xq28 which included AVPR2, the gene responsible for NDI; ARHGAP4, a hematopoietic specific gene encoding a GTPase-activating protein; and a highly conserved segment of DNA between ARHGAP4 and ARD1A, a gene involved in the response to hypoxia. Other patients with NDI, but without immunodeficiency, have had deletions that remove all ARHGAP4 except exon 1; however, no other patients have had deletions of the highly conserved intragenic region between ARHGAP4 and ARD1A. X chromosome inactivation studies, done on sorted cells from the mother and grandmother of the patient, carriers of the deletion, demonstrated exclusive use of the non-mutant X chromosome as the active X in CD4 and CD8 T cells. Surprisingly, NK cells, monocytes and neutrophils from these women demonstrated preferential use of the mutant X chromosome as the active X. These results are consistent with an X-linked form of SCID, due to the loss of regulatory elements that control the response to hypoxia in hematopoietic cells.
authors.affiliation: Department of Immunology, University of Tennessee College of Medicine, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA. maryellen.conley@stjude.org
authors.forename: Arnon
authors.initials: A
authors.lastname: Broides
authors.forename: Bettina H
authors.initials: BH
authors.lastname: Ault
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Arthus
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Bichet
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Conley
mesh_terms: D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D002675:Child, Preschool; D041321:Chromosomes, Human, X / Q000235:genetics*; D017124:Conserved Sequence; D018500:Diabetes Insipidus, Nephrogenic / Q000150:complications / Q000235:genetics*; D015536:Down-Regulation; D005091:Exons / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D050172:Genes, X-Linked; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D063209:N-Terminal Acetyltransferase A; D063213:N-Terminal Acetyltransferase E; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000378:metabolism; D017483:Receptors, Vasopressin / Q000235:genetics / Q000378:metabolism; D016511:Severe Combined Immunodeficiency / Q000150:complications / Q000235:genetics*
chemical_list: C446101:ARHGAP4 protein, human; D020690:GTPase-Activating Proteins; D039842:Neural Cell Adhesion Molecule L1; D017483:Receptors, Vasopressin; D000123:Acetyltransferases; D063209:N-Terminal Acetyltransferase A; C504824:NAA10 protein, human; D063213:N-Terminal Acetyltransferase E