title: Two unrelated patients with MRE11A mutations and Nijmegen breakage syndrome-like severe microcephaly.
abstract: MRE11 and NBS1 function together as components of a MRE11/RAD50/NBS1 protein complex, however deficiency of either protein does not result in the same clinical features. Mutations in the NBN gene underlie Nijmegen breakage syndrome (NBS), a chromosomal instability syndrome characterized by microcephaly, bird-like faces, growth and mental retardation, and cellular radiosensitivity. Additionally, mutations in the MRE11A gene are known to lead to an ataxia-telangiectasia-like disorder (ATLD), a late-onset, slowly progressive variant of ataxia-telangiectasia without microcephaly. Here we describe two unrelated patients with NBS-like severe microcephaly (head circumference -10.2 SD and -12.8 SD) and mutations in the MRE11A gene. Both patients were compound heterozygotes for a truncating or missense mutation and carried a translationally silent mutation. The truncating and missense mutations were assumed to be functionally debilitating. The translationally silent mutation common to both patients had an effect on splicing efficiency resulting in reduced but normal MRE11 protein. Their levels of radiation-induced activation of ATM were higher than those in ATLD cells.
authors.affiliation: Department of Genetics and Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi 1-2-3, Hiroshima 734-8553, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sakamoto
authors.forename: Hideki
authors.initials: H
authors.lastname: Izumi
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nakazawa
authors.forename: Tomoo
authors.initials: T
authors.lastname: Ogi
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Tahara
authors.forename: Shozo
authors.initials: S
authors.lastname: Oku
authors.forename: Azuma
authors.initials: A
authors.lastname: Hiramoto
authors.forename: Toshihide
authors.initials: T
authors.lastname: Shiiki
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Fujisawa
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ohashi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sakemi
authors.forename: Shinya
authors.initials: S
authors.lastname: Matsuura
mesh_terms: D000293:Adolescent; D000328:Adult; D001072:Apraxias / Q000201:enzymology / Q000378:metabolism; D001260:Ataxia Telangiectasia / Q000201:enzymology / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D053148:Caspase 3 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000235:genetics; D002524:Cerebellar Ataxia / Q000151:congenital; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D016195:G2 Phase / Q000235:genetics; D006801:Humans; D034141:Hypoalbuminemia / Q000201:enzymology / Q000378:metabolism; D007223:Infant; D000076228:MRE11 Homologue Protein; D008297:Male; D008831:Microcephaly / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D009154:Mutation; D049932:Nijmegen Breakage Syndrome / Q000473:pathology*; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011836:Radiation Tolerance / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D000076228:MRE11 Homologue Protein; D053148:Caspase 3