Mutations in βB3-Crystallin Associated with Autosomal Recessive Cataract in Two Pakistani Families

Riazuddin, Sheikh; Yasmeen, Aneela; Yao, Wenliang; Sergeev, Yuri V.; Zhang, Qingjiong; Zulfiqar, Fareeha; Riaz, Assad; Hejtmancik, J. Fielding

doi:10.1167/iovs.04-1481

Cited by 71 publications

(46 citation statements)

References 32 publications

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“…These observations suggest that βBB2-crystallin has an important biological function in addition to the structural and refractive role of a crystallin. This is supported when taken in conjunction with the existence of autosomal recessive forms of cataract resulting from mutations in βB1-and βB3-crystallins [48], [49] and the mild nature of heterozygous βB2-crystallin cataracts when compared to the homozygous state [50]. These findings suggest that this might be the case for the other basic β-crystallins as well.…”

Section: Lens Crystallinsmentioning

confidence: 64%

Congenital cataracts and their molecular genetics

Hejtmancik¹

2008

Seminars in Cell & Developmental Biology

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Cataract can be defined as any opacity of the crystalline lens. Congenital cataract is particularly serious because it has the potential for inhibiting visual development, resulting in permanent blindness. Inherited cataracts represent a major contribution to congenital cataracts, especially in developed countries. While cataract represents a common end stage of mutations in a potentially large number of genes acting through varied mechanisms in practice most inherited cataracts have been associated with a subgroup of genes encoding proteins of particular importance for the maintenance of lens transparency and homeostasis. The increasing availability of more detailed information about these proteins and their functions and is making it possible to understand the pathophysiology of cataracts and the biology of the lens in general. Transparency and the LensThe lens transmits light with wavelengths from 390 nm to 1200 nm efficiently, extending well above the limit of visual perception (about 720 nm). Lens transparency results from appropriate architecture of lens cells and tight packing of their proteins, resulting in a constant refractive index over distances approximating the wavelength of light [1], [2]. Ultrastructurally, the lens comprises an anterior layer of organelle rich cuboidal epithelial cells covering a large fiber cell mass making up the bulk of the lens (Fig. 1). Layers of nucleated cortical fiber cells form highly ordered concentric shells around the nonnucleated and essentially organelle-free central fiber cells which make up the lens nucleus. The ends of the more peripheral fiber cells abut in branched anterior and posterior sutures. The cellular architecture and arrangement of the fiber cells and particularly their sutures are critical for light transmission and lens transparency [3]. In addition, the stability and close ordering of lens crystallins, which make up 80−90% of the soluble proteins in the lens, are critical for lens transparency. The high protein content of the lens and especially the lens nucleus, approximately 60% of the wet weight --the highest of any tissue, is particularly important for refraction and focusing of light. Solutions of lens crystallins are highly transparent, and as they are concentrated to levels above 450 mg/ml, light scattering actually decreases [4], [5].Cataracts, which can be defined as lens opacities, have multiple causes, but are often associated with breakdown of the lens microarchitecture [3], [6], possibly including vacuole formation and disarray of lens cells, which can cause large fluctuations in density resulting in light scattering. In addition, light scattering and opacity will occur if there is a significant amount of high molecular weight protein aggregates of approximately 1000 Å or more in size [7], [8]. The short-range ordered packing of the lens crystallins is important in this regard. For transparency, crystallins must exist in a homogeneous phase with significant short-range spatial Publisher's Disclaimer: This is a PDF file of an un...

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Section: Lens Crystallinsmentioning

confidence: 64%

Congenital cataracts and their molecular genetics

Hejtmancik¹

2008

Seminars in Cell & Developmental Biology

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284

248

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“…Nor have there been reports of autosomal recessive mutations in the CRYBA genes (CRYBA1 and CRYBA4) or CRYG genes (CRYGC , CRYGD and CRYGS) , previously associated with human CC. It appears that the crystallins most frequently mutated in arCC are the αA-crystallins CRYAA and CRYAB [145][146][147] and the βB-crystallins CRYBB1 [12, 148,149] and CRYBB3 [150] . In an attempt to establish the contribution of each of the crystallin classes to CC in Indian patients, Devi et al [134] screened all 10 CCassociated crystallin genes in 60 families from South India.…”

Section: Crystallin Mutationsmentioning

confidence: 99%

The Use of Autozygosity Mapping and Next-Generation Sequencing in Understanding Anterior Segment Defects Caused by an Abnormal Development of the Lens

Gillespie

Lloyd²,

Black

2014

Hum Hered

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The formation of the anterior segment of the eye is an intricate process that is dependent to a large degree on the normal development of the lens. Despite intensive study of the role of well-described eye genes, many causes of lenticular and anterior segment anomalies remain elusive. The majority of genes implicated thus far act in an autosomal dominant manner. Autosomal recessive causes are less well described; their diagnosis has been hindered by technological limitations, extreme genetic heterogeneity, a lack of understanding of eye biology and the role of many genes within the genome. The opportunity for the discovery of extremely rare autosomal recessive causes of ocular abnormalities from the study of consanguineous families is large, particularly through the powerful combination of next-generation sequencing with autozygosity mapping. Having begun to overcome the genetic heterogeneity bottleneck, it is increasingly recognised that the interpretation of genetic variants and the association of novel genes with a particular phenotype remain challenging. Nonetheless, increasing understanding of the genetic and mutational basis of lens and anterior segment abnormalities will be of enormous value to our comprehension of eye disease(s). Further, it will improve our ability to accurately interpret putative disease-causing variants with the aim of providing more personalised patient care and avoiding lifelong visual loss in children.

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“…At least 34 loci in the human genome have been reported to be associated with various forms of pediatric cataract. Autosomal dominant and recessive forms of cataracts have been caused by mutations in 22 different genes encoding crystallins CRYAA [ 40 ], CRYAB [ 41 ], CRYBA1 [ 42 ], CRYBA4 [ 43 ], CRYBB1 [ 44 ], CRYBB2 [ 45 ], CRYBB3 [ 46 ], CRYGC, CRYGD [ 47 ], and CRYGS [ 48 ], cytoskeletal proteins BFSP1 [ 49 ] and BFSP2 [ 50 ], membrane proteins GJA3 [ 51 ] and GJA8 [ 52 ], MIP [ 53 ] and LIM2 [ 54 ], transcription factors HSF4 [ 55 ], PITX3 [ 56 ], and MAF [ 57 ], glucosaminyl ( N -acetyl) transferase 2 (GCNT2) [ 58 ], chromatin modifying protein-4B CHMP4B [ 59 ] and TMEM114 [ 60 ] (Table 16.2 ). On the basis of current studies, mutations in about half of the affected families occurs in crystallin gene, a quarter in connexins and the remaining is evenly split between membrane proteins, intermediate fi lament proteins, and transcription factors.…”

Section: Cataract: a Progressive Deterioration Of Visionmentioning

confidence: 99%