title: Characterization of a familial t(16;22) balanced translocation associated with congenital cataract leads to identification of a novel gene, TMEM114, expressed in the lens and disrupted by the translocation.
abstract: Molecular characterization of chromosomal rearrangements is a powerful resource in identification of genes associated with monogenic disorders. We describe the molecular characterization of a balanced familial chromosomal translocation, t(16;22)(p13.3;q11.2), segregating with congenital lamellar cataract. This led to the discovery of a cluster of lens-derived expressed sequence tags (ESTs) close to the 16p13.3 breakpoint. This region harbors a locus associated with cataract and microphthalmia. Long-range PCR and 16p13.3 breakpoint sequencing identified genomic sequence in a human genome sequence gap, and allowed identification of a novel four-exon gene, designated TMEM114, which encodes a predicted protein of 223 amino acids. The breakpoint lies in the promoter region of TMEM114 and separates the gene from predicted eye-specific upstream transcription factor binding sites. There is sequence conservation among orthologs down to zebrafish. The protein is predicted to contain four transmembrane domains with homology to the lens intrinsic membrane protein, LIM2 (also known as MP20), in the PMP-22/EMP/MP20 family. TMEM114 mutation screening in 130 congenital cataract patients revealed missense mutations leading to the exchange of highly-conserved amino acids in the first extracellular domain of the protein (p.I35T, p.F106L) in two separate patients and their reportedly healthy sibling and mother, respectively. In the lens, Tmem114 shows expression in the lens epithelial cells extending into the transitional zone where early fiber differentiation occurs. Our findings implicate dysregulation of expression of this novel human gene, TMEM114, in mammalian cataract formation.
authors.affiliation: Academic Unit of Medical Genetics and Regional Genetic Service, University of Manchester, St. Mary's Hospital, Manchester, United Kingdom. rjamieson@cmri.usyd.edu.au
authors.forename: Robyn V
authors.initials: RV
authors.lastname: Jamieson
authors.forename: Nicola
authors.initials: N
authors.lastname: Farrar
authors.forename: Katrina
authors.initials: K
authors.lastname: Stewart
authors.forename: Rahat
authors.initials: R
authors.lastname: Perveen
authors.forename: Marija
authors.initials: M
authors.lastname: Mihelec
authors.forename: Martin
authors.initials: M
authors.lastname: Carette
authors.forename: John R
authors.initials: JR
authors.lastname: Grigg
authors.forename: John W
authors.initials: JW
authors.lastname: McAvoy
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Lovicu
authors.forename: Patrick P L
authors.initials: PP
authors.lastname: Tam
authors.forename: Peter
authors.initials: P
authors.lastname: Scambler
authors.forename: I Christopher
authors.initials: IC
authors.lastname: Lloyd
authors.forename: Dian
authors.initials: D
authors.lastname: Donnai
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Black
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002386:Cataract / Q000235:genetics*; D002875:Chromosomes / Q000648:ultrastructure*; D002885:Chromosomes, Human, Pair 16; D002892:Chromosomes, Human, Pair 22; D020224:Expressed Sequence Tags; D005260:Female; D006801:Humans; D007908:Lens, Crystalline / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D010375:Pedigree; D014178:Translocation, Genetic
chemical_list: D008565:Membrane Proteins; C523698:TMEM114 protein, human