[CRGD_HUMAN] Defects in CRYGD are a cause of cataract autosomal dominant (ADC) [MIM:604219]. Cataract is an opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. In general, the more posteriorly located and dense an opacity, the greater the impact on visual function. Cataract is the most common treatable cause of visual disability in childhood. Defects in CRYGD are the cause of cataract congenital non-nuclear polymorphic autosomal dominant (CCP) [MIM:601286]; also known as polymorphic congenital cataract. A congenital cataract characterized by a non-progressive phenotype and partial opacity that has a variable location between the fetal nucleus of the lens and the equator. The fetal nucleus is normal. The opacities are irregular and look similar to a bunch of grapes and may be present simultaneously in different lens layers. Defects in CRYGD are the cause of cataract congenital cerulean type 3 (CCA3) [MIM:608983]; also known as congenital cataract blue dot type 3. A cerulean form of autosomal dominant congenital cataract. Cerulean cataract is characterized by peripheral bluish and white opacifications organized in concentric layers with occasional central lesions arranged radially. The opacities are observed in the superficial layers of the fetal nucleus as well as the adult nucleus of the lens. Involvement is usually bilateral. Visual acuity is only mildly reduced in childhood. In adulthood, the opacifications may progress, making lens extraction necessary. Histologically the lesions are described as fusiform cavities between lens fibers which contain a deeply staining granular material. Although the lesions may take on various colors, a dull blue is the most common appearance and is responsible for the designation cerulean cataract. Defects in CRYGD are the cause of cataract crystalline aculeiform (CACA) [MIM:115700]. A congenital crystalline cataract characterized by fiberglass-like or needle-like crystals projecting in different directions, through or close to the axial region of the lens. The opacity causes a variable degree of vision loss.
[CRGD_HUMAN] Crystallins are the dominant structural components of the vertebrate eye lens.
We describe a 5-year-old boy with a unique congenital cataract caused by deposition of numerous birefringent, pleiochroic and macroscopically prismatic crystals. Crystal analysis with subsequent automatic Edman degradation and matrix-associated laser desorption ionization time-of-flight mass spectrometry have identified the crystal-forming protein as gammaD-crystallin (CRYGD) lacking the N-terminal methionine. Sequencing of the CRYGD gene has shown a heterozygous C-->A transversion in position 109 of the inferred cDNA (36R-->S transversion of the processed, N-terminal methionine-lacking CRYGD). The lens protein crystals were X-ray diffracting, and our crystal structure solution at 2.25 A suggests that mutant R36S CRYGD has an unaltered protein fold. In contrast, the observed crystal packing is possible only with the mutant protein molecules that lack the bulky Arg36 side chain. This is the first described case of human cataract caused by crystallization of a protein in the lens. It involves the third known mutation in the CRYGD gene but offers, for the first time, a causative explanation of the phenotype.
Link between a novel human gammaD-crystallin allele and a unique cataract phenotype explained by protein crystallography.,Kmoch S, Brynda J, Asfaw B, Bezouska K, Novak P, Rezacova P, Ondrova L, Filipec M, Sedlacek J, Elleder M Hum Mol Genet. 2000 Jul 22;9(12):1779-86. PMID:10915766
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
↑ Stephan DA, Gillanders E, Vanderveen D, Freas-Lutz D, Wistow G, Baxevanis AD, Robbins CM, VanAuken A, Quesenberry MI, Bailey-Wilson J, Juo SH, Trent JM, Smith L, Brownstein MJ. Progressive juvenile-onset punctate cataracts caused by mutation of the gammaD-crystallin gene. Proc Natl Acad Sci U S A. 1999 Feb 2;96(3):1008-12. PMID:9927684
↑ Pande A, Pande J, Asherie N, Lomakin A, Ogun O, King JA, Lubsen NH, Walton D, Benedek GB. Molecular basis of a progressive juvenile-onset hereditary cataract. Proc Natl Acad Sci U S A. 2000 Feb 29;97(5):1993-8. PMID:10688888 doi:10.1073/pnas.040554397
↑ Wang B, Yu C, Xi YB, Cai HC, Wang J, Zhou S, Zhou S, Wu Y, Yan YB, Ma X, Xie L. A novel CRYGD mutation (p.Trp43Arg) causing autosomal dominant congenital cataract in a Chinese family. Hum Mutat. 2011 Jan;32(1):E1939-47. doi: 10.1002/humu.21386. PMID:21031598 doi:10.1002/humu.21386
↑ Messina-Baas OM, Gonzalez-Huerta LM, Cuevas-Covarrubias SA. Two affected siblings with nuclear cataract associated with a novel missense mutation in the CRYGD gene. Mol Vis. 2006 Aug 24;12:995-1000. PMID:16943771
↑ Plotnikova OV, Kondrashov FA, Vlasov PK, Grigorenko AP, Ginter EK, Rogaev EI. Conversion and compensatory evolution of the gamma-crystallin genes and identification of a cataractogenic mutation that reverses the sequence of the human CRYGD gene to an ancestral state. Am J Hum Genet. 2007 Jul;81(1):32-43. Epub 2007 May 16. PMID:17564961 doi:S0002-9297(07)62814-6
↑ Heon E, Priston M, Schorderet DF, Billingsley GD, Girard PO, Lubsen N, Munier FL. The gamma-crystallins and human cataracts: a puzzle made clearer. Am J Hum Genet. 1999 Nov;65(5):1261-7. PMID:10521291 doi:10.1086/302619
↑ Kmoch S, Brynda J, Asfaw B, Bezouska K, Novak P, Rezacova P, Ondrova L, Filipec M, Sedlacek J, Elleder M. Link between a novel human gammaD-crystallin allele and a unique cataract phenotype explained by protein crystallography. Hum Mol Genet. 2000 Jul 22;9(12):1779-86. PMID:10915766