title: Mutations in SCO2 are associated with autosomal-dominant high-grade myopia.
abstract: Myopia, or near-sightedness, is an ocular refractive error of unfocused image quality in front of the retinal plane. Individuals with high-grade myopia (dioptric power greater than -6.00) are predisposed to ocular morbidities such as glaucoma, retinal detachment, and myopic maculopathy. Nonsyndromic, high-grade myopia is highly heritable, and to date multiple gene loci have been reported. We performed exome sequencing in 4 individuals from an 11-member family of European descent from the United States. Affected individuals had a mean dioptric spherical equivalent of -22.00 sphere. A premature stop codon mutation c.157C>T (p.Gln53*) cosegregating with disease was discovered within SCO2 that maps to chromosome 22q13.33. Subsequent analyses identified three additional mutations in three highly myopic unrelated individuals (c.341G>A, c.418G>A, and c.776C>T). To determine differential gene expression in a developmental mouse model, we induced myopia by applying a -15.00D lens over one eye. Messenger RNA levels of SCO2 were significantly downregulated in myopic mouse retinae. Immunohistochemistry in mouse eyes confirmed SCO2 protein localization in retina, retinal pigment epithelium, and sclera. SCO2 encodes for a copper homeostasis protein influential in mitochondrial cytochrome c oxidase activity. Copper deficiencies have been linked with photoreceptor loss and myopia with increased scleral wall elasticity. Retinal thinning has been reported with an SC02 variant. Human mutation identification with support from an induced myopic animal provides biological insights of myopic development.
authors: Duke Center for Human Genetics, 905 S LaSalle Street, Durham, NC 27710, USA.
authors: Khanh-Nhat
authors: KN
authors: Tran-Viet
authors: Caldwell
authors: C
authors: Powell
authors: Veluchamy A
authors: VA
authors: Barathi
authors: Thomas
authors: T
authors: Klemm
authors: Sebastian
authors: S
authors: Maurer-Stroh
authors: Vachiranee
authors: V
authors: Limviphuvadh
authors: Vincent
authors: V
authors: Soler
authors: Candice
authors: C
authors: Ho
authors: Tammy
authors: T
authors: Yanovitch
authors: Georg
authors: G
authors: Schneider
authors: Yi-Ju
authors: YJ
authors: Li
authors: Erica
authors: E
authors: Nading
authors: Ravikanth
authors: R
authors: Metlapally
authors: Seang-Mei
authors: SM
authors: Saw
authors: Liang
authors: L
authors: Goh
authors: Steve
authors: S
authors: Rozen
authors: Terri L
authors: TL
authors: Young
mesh_terms: D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D018389:Codon, Nonsense / Q000235:genetics; D003300:Copper / Q000378:metabolism; D059472:Exome / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D005799:Genes, Dominant / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics*; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D009216:Myopia / Q000235:genetics* / Q000473:pathology; D017354:Point Mutation / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014481:United States; D044465:White People / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D018389:Codon, Nonsense; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D012333:RNA, Messenger; C400285:SCO2 protein, human; D003300:Copper
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