title: Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy.
abstract: X-linked infantile spinal muscular atrophy (XL-SMA) is an X-linked disorder presenting with the clinical features hypotonia, areflexia, and multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells and infantile death. To identify the XL-SMA disease gene, we performed large-scale mutation analysis in genes located between markers DXS8080 and DXS7132 (Xp11.3-Xq11.1). This resulted in detection of three rare novel variants in exon 15 of UBE1 that segregate with disease: two missense mutations (c.1617 G-->T, p.Met539Ile; c.1639 A-->G, p.Ser547Gly) present each in one XL-SMA family, and one synonymous C-->T substitution (c.1731 C-->T, p.Asn577Asn) identified in another three unrelated families. Absence of the missense mutations was demonstrated for 3550 and absence of the synonymous mutation was shown in 7914 control X chromosomes; therefore, these results yielded statistical significant evidence for the association of the synonymous substitution and the two missense mutations with XL-SMA (p = 2.416 x 10(-10), p = 0.001815). We also demonstrated that the synonymous C-->T substitution leads to significant reduction of UBE1 expression and alters the methylation pattern of exon 15, implying a plausible role of this DNA element in developmental UBE1 expression in humans. Our observations indicate first that XL-SMA is part of a growing list of neurodegenerative disorders associated with defects in the ubiquitin-proteasome pathway and second that synonymous C-->T transitions might have the potential to affect gene expression.
authors.affiliation: Department of Obstetrics and Gynecology, Technical University Munich, 81675 Munich, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Ramser
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Ahearn
authors.forename: Claus
authors.initials: C
authors.lastname: Lenski
authors.forename: Kemal O
authors.initials: KO
authors.lastname: Yariz
authors.forename: Heide
authors.initials: H
authors.lastname: Hellebrand
authors.forename: Michael
authors.initials: M
authors.lastname: von Rhein
authors.forename: Robin D
authors.initials: RD
authors.lastname: Clark
authors.forename: Rita K
authors.initials: RK
authors.lastname: Schmutzler
authors.forename: Peter
authors.initials: P
authors.lastname: Lichtner
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
authors.forename: Alfons
authors.initials: A
authors.lastname: Meindl
authors.forename: Lisa
authors.initials: L
authors.lastname: Baumbach-Reardon
mesh_terms: D004252:DNA Mutational Analysis; D005260:Female; D050172:Genes, X-Linked; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D017354:Point Mutation; D014897:Spinal Muscular Atrophies of Childhood / Q000235:genetics*; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics*
chemical_list: C471538:UBA1 protein, human; D044764:Ubiquitin-Activating Enzymes