title: Identification of mutations in two major mRNA isoforms of the Chediak-Higashi syndrome gene in human and mouse.
abstract: Chediak-Higashi syndrome is an autosomal recessive, immune deficiency disorder of human (CHS) and mouse (beige, bg) that is characterized by abnormal intracellular protein transport to, and from, the lysosome. Recent reports have described the identification of homologous genes that are mutated in human CHS and bg mice. Here we report the sequences of two major mRNA isoforms of the CHS gene in human and mouse. These isoforms differ both in size and in sequence at the 3' end of their coding domains, with the smaller isoform (approximately 5.8 kb) arising from incomplete splicing and reading through an intron. These mRNAs also differ in tissue distribution of transcription and in predicted biological properties. Novel mutations were identified within the region of the coding domain common to both isoforms in three CHS patients: C-->T transitions that generated stop codons (R50X and Q1029X) were found in two patients, and a novel frameshift mutation (deletion of nucleotides 3073 and 3074 of the coding domain) was found in a third. Northern blots of lymphoblastoid mRNA from CHS patients revealed loss of the largest transcript (approximately 13.5 kb) in two of seven CHS patients, while the small mRNA was undiminished in abundance. These results suggest that the small isoform alone cannot complement Chediak-Higashi syndrome.
authors.affiliation: Department of Medicine, Center for Mammalian Genetics, University of Florida, Gainesville 32610-0221, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Barbosa
authors.forename: F J
authors.initials: FJ
authors.lastname: Barrat
authors.forename: V T
authors.initials: VT
authors.lastname: Tchernev
authors.forename: Q A
authors.initials: QA
authors.lastname: Nguyen
authors.forename: V S
authors.initials: VS
authors.lastname: Mishra
authors.forename: S D
authors.initials: SD
authors.lastname: Colman
authors.forename: E
authors.initials: E
authors.lastname: Pastural
authors.forename: R
authors.initials: R
authors.lastname: Dufourcq-Lagelouse
authors.forename: A
authors.initials: A
authors.lastname: Fischer
authors.forename: R F
authors.initials: RF
authors.lastname: Holcombe
authors.forename: M R
authors.initials: MR
authors.lastname: Wallace
authors.forename: S J
authors.initials: SJ
authors.lastname: Brandt
authors.forename: G
authors.initials: G
authors.lastname: de Saint Basile
authors.forename: S F
authors.initials: SF
authors.lastname: Kingsmore
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D002609:Chediak-Higashi Syndrome / Q000235:genetics*; D004252:DNA Mutational Analysis; D018076:DNA, Complementary; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007536:Isomerism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger; D017386:Sequence Homology, Amino Acid; D014018:Tissue Distribution; D033921:Vesicular Transport Proteins
chemical_list: D018076:DNA, Complementary; D047908:Intracellular Signaling Peptides and Proteins; C102161:LYST protein, human; C491133:Lyst protein, mouse; D011506:Proteins; D012333:RNA, Messenger; D033921:Vesicular Transport Proteins