title: Allelic heterogeneity of SMARD1 at the IGHMBP2 locus.
abstract: Spinal Muscular Atrophy with Respiratory Distress (SMARD) is an autosomal recessive disorder characterized by neurogenic muscular atrophy due to progressive anterior horn cell degeneration and early life-threatening respiratory failure ascribed to diaphragmatic dysfunction. SMARD is clinically and genetically heterogeneous. SMARD type 1 is characterized by onset of respiratory failure within the first weeks of life and has been ascribed to mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2) gene on chromosome 11q13-q21. We report here the identification of nine novel IGHMBP2 mutations in five SMARD1 patients, including seven missense [ c.587A>G (p.Gln196Arg), c.647C>T (p.Pro216Leu), c.752T>C (p.Leu251Pro), c.1693G>A (p.Asp565Asn), c.1730T>C (p.Leu577Pro), c.1807C>T (p.Arg603Cys), c.1909C>T (p.Arg637Cys)] and two nonsense mutations [ c.1488C>A (p.Cys496X), c.2368C>T (p.Arg790X)]. Interestingly, 7 of 9 mutations occurred at highly conserved residues of the putative DNA helicase domain. The identification of novel IGHMBP2 variants will hopefully help diagnosing SMARD1 and contribute to a better functional characterization of IGHMBP2 gene product.
authors.affiliation: INSERM U393 and Department of Genetics, Hospital Necker Enfants Malades, Paris, France.
authors.forename: I
authors.initials: I
authors.lastname: Maystadt
authors.forename: M
authors.initials: M
authors.lastname: Zarhrate
authors.forename: P
authors.initials: P
authors.lastname: Landrieu
authors.forename: O
authors.initials: O
authors.lastname: Boespflug-Tanguy
authors.forename: S
authors.initials: S
authors.lastname: Sukno
authors.forename: P
authors.initials: P
authors.lastname: Collignon
authors.forename: J
authors.initials: J
authors.lastname: Melki
authors.forename: C
authors.initials: C
authors.lastname: Verellen-Dumoulin
authors.forename: A
authors.initials: A
authors.lastname: Munnich
authors.forename: L
authors.initials: L
authors.lastname: Viollet
mesh_terms: D000483:Alleles; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D009154:Mutation; D014897:Spinal Muscular Atrophies of Childhood / Q000175:diagnosis / Q000235:genetics*