title: Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1.
abstract: Classic spinal muscular atrophy (SMA) is caused by mutations in the telomeric copy of SMN1. Its product is involved in various cellular processes, including cytoplasmic assembly of spliceosomal small nuclear ribonucleoproteins, pre-mRNA processing and activation of transcription. Spinal muscular atrophy with respiratory distress (SMARD) is clinically and genetically distinct from SMA. Here we demonstrate that SMARD type 1 (SMARD1) results from mutations in the gene encoding immunoglobulin micro-binding protein 2 (IGHMBP2; on chromosome 11q13.2-q13.4). In six SMARD1 families, we detected three recessive missense mutations (exons 5, 11 and 12), two nonsense mutations (exons 2 and 5), one frameshift deletion (exon 5) and one splice donor-site mutation (intron 13). Mutations in mouse Ighmbp2 (ref. 14) have been shown to be responsible for spinal muscular atrophy in the neuromuscular degeneration (nmd) mouse, whose phenotype resembles the SMARD1 phenotype. Like the SMN1 product, IGHMBP2 colocalizes with the RNA-processing machinery in both the cytoplasm and the nucleus. Our results show that IGHMBP2 is the second gene found to be defective in spinal muscular atrophy, and indicate that IGHMBP2 and SMN share common functions important for motor neuron maintenance and integrity in mammals.
authors.affiliation: Department of Neuropediatrics, Charité, Campus Virchow-Klinikum, Humboldt University, 13353 Berlin, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Grohmann
authors.forename: M
authors.initials: M
authors.lastname: Schuelke
authors.forename: A
authors.initials: A
authors.lastname: Diers
authors.forename: K
authors.initials: K
authors.lastname: Hoffmann
authors.forename: B
authors.initials: B
authors.lastname: Lucke
authors.forename: C
authors.initials: C
authors.lastname: Adams
authors.forename: E
authors.initials: E
authors.lastname: Bertini
authors.forename: H
authors.initials: H
authors.lastname: Leonhardt-Horti
authors.forename: F
authors.initials: F
authors.lastname: Muntoni
authors.forename: R
authors.initials: R
authors.lastname: Ouvrier
authors.forename: A
authors.initials: A
authors.lastname: Pfeufer
authors.forename: R
authors.initials: R
authors.lastname: Rossi
authors.forename: L
authors.initials: L
authors.lastname: Van Maldergem
authors.forename: J M
authors.initials: JM
authors.lastname: Wilmshurst
authors.forename: T F
authors.initials: TF
authors.lastname: Wienker
authors.forename: M
authors.initials: M
authors.lastname: Sendtner
authors.forename: S
authors.initials: S
authors.lastname: Rudnik-Schöneborn
authors.forename: K
authors.initials: K
authors.lastname: Zerres
authors.forename: C
authors.initials: C
authors.lastname: Hübner
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11; D017931:DNA Primers; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D012127:Respiratory Distress Syndrome, Newborn / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors
chemical_list: D002352:Carrier Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; C489892:IGHMBP2 protein, human; C081225:Ighmbp2 protein, mouse; D014157:Transcription Factors