The structure of the cataract causing P23T mutant of human gamma-D crystallin
[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.
Publication Abstract from PubMed
Crystallins are major proteins of the eye lens and essential for lens transparency. Mutations and aging of crystallins cause cataracts, the predominant cause of blindness in the world. In human gamma-D crystallin, the P23T mutant is associated with congenital cataracts. Up to now, no atomic structural information has been available for this variant. Biophysical analyses of this mutant protein have revealed dramatically reduced solubility compared to wild type protein due to self-association into higher molecular weight clusters and aggregates that retain a native-like conformation within the monomers (Pande et al. (2005) Biochemistry 44, 2491-2500). To elucidate the structure and local conformation around the mutation site, we have determined the solution structure and characterized the protein's dynamic behavior by NMR. Although the global structure is very similar to the X-ray structure of wild-type gamma-D crystallin, pivotal local conformational and dynamic differences are caused by the threonine substitution. In particular, in the P23T mutant, the imidazole ring of His22 switches from the predominant Nepsilon2 tautomer in the wild-type protein to the Nepsilon1 tautomer and an altered motional behavior of the associated region in the protein is observed. The data support structural changes that may initiate aggregation or polymerization by the mutant protein.
The structure of the cataract causing P23T mutant of HgD crystallin exhibits local distinctive conformational and dynamic changes.,Jung J, Byeon IJ, Wang Y, King J, Gronenborn A Biochemistry. 2009 Feb 13. PMID:19216553
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.