title: Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I.
abstract: Small nuclear RNAs (snRNAs) are essential factors in messenger RNA splicing. By means of homozygosity mapping and deep sequencing, we show that a gene encoding U4atac snRNA, a component of the minor U12-dependent spliceosome, is mutated in individuals with microcephalic osteodysplastic primordial dwarfism type I (MOPD I), a severe developmental disorder characterized by extreme intrauterine growth retardation and multiple organ abnormalities. Functional assays showed that mutations (30G>A, 51G>A, 55G>A, and 111G>A) associated with MOPD I cause defective U12-dependent splicing. Endogenous U12-dependent but not U2-dependent introns were found to be poorly spliced in MOPD I patient fibroblast cells. The introduction of wild-type U4atac snRNA into MOPD I cells enhanced U12-dependent splicing. These results illustrate the critical role of minor intron splicing in human development.
authors.affiliation: Human Cancer Genetics Program, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Huiling
authors.initials: H
authors.lastname: He
authors.forename: Sandya
authors.initials: S
authors.lastname: Liyanarachchi
authors.forename: Keiko
authors.initials: K
authors.lastname: Akagi
authors.forename: Rebecca
authors.initials: R
authors.lastname: Nagy
authors.forename: Jingfeng
authors.initials: J
authors.lastname: Li
authors.forename: Rosemary C
authors.initials: RC
authors.lastname: Dietrich
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Nikhil
authors.initials: N
authors.lastname: Sebastian
authors.forename: Bernard
authors.initials: B
authors.lastname: Wen
authors.forename: Baozhong
authors.initials: B
authors.lastname: Xin
authors.forename: Jarnail
authors.initials: J
authors.lastname: Singh
authors.forename: Pearlly
authors.initials: P
authors.lastname: Yan
authors.forename: Hansjuerg
authors.initials: H
authors.lastname: Alder
authors.forename: Eric
authors.initials: E
authors.lastname: Haan
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.forename: Beate
authors.initials: B
authors.lastname: Albrecht
authors.forename: Erik
authors.initials: E
authors.lastname: Puffenberger
authors.forename: Heng
authors.initials: H
authors.lastname: Wang
authors.forename: Judith A
authors.initials: JA
authors.lastname: Westman
authors.forename: Richard A
authors.initials: RA
authors.lastname: Padgett
authors.forename: David E
authors.initials: DE
authors.lastname: Symer
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
mesh_terms: D002460:Cell Line; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D004392:Dwarfism / Q000235:genetics / Q000378:metabolism; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007438:Introns; D055029:Inverted Repeat Sequences; D008297:Male; D008831:Microcephaly / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009690:Nucleic Acid Conformation; D010009:Osteochondrodysplasias / Q000235:genetics / Q000378:metabolism; D010375:Pedigree; D012326:RNA Splicing; D012342:RNA, Small Nuclear / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017381:Spliceosomes / Q000235:genetics* / Q000378:metabolism
chemical_list: D012342:RNA, Small Nuclear; C096986:U12 small nuclear RNA; C405484:U2 small nuclear RNA; C405482:U4 small nuclear RNA