A Homozygous Splice Mutation in the<i>HSF4</i>Gene Is Associated with an Autosomal Recessive Congenital Cataract

Smaoui, Nizar; Beltaief, O.; Benhamed, Sonia; Mrad, Ridha; Mâazoul, Faouzi; Ouertani, A.; Chaâbouni, Habiba; Hejtmancik, J. Fielding

doi:10.1167/iovs.03-1370

Cited by 87 publications

(66 citation statements)

References 21 publications

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“…Mutations in HSF4 have been associated with both autosomal dominant and recessive cataracts. The dominant cataracts present in early childhood and are described as lamellar [70], including the historically important Marner family cataract [71], whereas, the recessive cataracts had a congenital onset and ranged in severity from nuclear with some cortical involvement [72] to total lens opacities at birth with associated nystagmus [73]. Interestingly, the dominant mutations in HSF4 lie within the α-helical DNA-binding domain, whereas, the recessive mutations lie outside this highly conserved functional domain.…”

Section: Growth and Transcription Factorsmentioning

confidence: 99%

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: Growth and Transcription Factorsmentioning

confidence: 99%

Congenital cataracts and their molecular genetics

Hejtmancik¹

2008

Seminars in Cell & Developmental Biology

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284

248

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“…In humans, mutations in HSF4 are associated with various recessive and dominant forms of congenital and age-related cataracts [109][110][111][112][113][114][115]. Similarly, the Hsf4 knockout mice (Hsf4 2/2 ) develop cataracts.…”

Section: Genes Causing Juvenile Cataractmentioning

confidence: 99%

Clinical and experimental advances in congenital and paediatric cataracts

Churchill

Graw

2011

Phil. Trans. R. Soc. B

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Cataracts (opacities of the lens) are frequent in the elderly, but rare in paediatric practice. Congenital cataracts (in industrialized countries) are mainly caused by mutations affecting lens development. Much of our knowledge about the underlying mechanisms of cataractogenesis has come from the genetic analysis of affected families: there are contributions from genes coding for transcription factors (such as FoxE3, Maf, Pitx3) and structural proteins such as crystallins or connexins. In addition, there are contributions from enzymes affecting sugar pathways (particularly the galactose pathway) and from a quite unexpected area: axon guidance molecules like ephrins and their receptors. Cataractous mouse lenses can be identified easily by visual inspection, and a remarkable number of mutant lines have now been characterized. Generally, most of the mouse mutants show a similar phenotype to their human counterparts; however, there are some remarkable differences. It should be noted that many mutations affect genes that are expressed not only in the lens, but also in tissues and organs outside the eye. There is increasing evidence for pleiotropic effects of these genes, and increasing consideration that cataracts may act as early and readily detectable biomarkers for a number of systemic syndromes.

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“…This is consistent with other studies that have identified an important role for mammalian HSF4 in lens development and differentiation of lens fibers. Mutations in HSF4 genes have been linked to several human families with hereditary congenital cataracts as well as several dog breeds that also frequently exhibit juvenile cataracts (Bu et al 2002;Smaoui et al 2004;Ke et al 2006;Mellersh et al 2006;Engelhardt et al 2007). Several of these mutations occur in the DNA binding domain of the protein and affect the ability of HSF4 to bind to HSE sequences .…”

Section: Discussionmentioning

confidence: 99%

“…The reduced severity of the small eye phenotype in the hsf1 knockdowns suggested that there are likely other factors involved in regulating hsp70 expression in the zebrafish lens. Both HSF1 and HSF4 play a role in mammalian lens development (Fujimoto et al 2004;Min et al 2004;Smaoui et al 2004;Mellersh et al 2006;Fujimoto et al 2008;Shi et al 2009;Abane and Mezger 2010), suggesting that the zebrafish hsf4 recently identified in an expressed sequence tag (EST) library could play a similar role. Here, we have carried out a comparative sequence analysis of zebrafish HSF4 to zebrafish HSF1 and HSF2, as well as HSFs from a wide range of organisms.…”

Section: Introductionmentioning

confidence: 99%

Zebrafish HSF4: a novel protein that shares features of both HSF1 and HSF4 of mammals

Swan

Evans

Sylvain

et al. 2012

Cell Stress and Chaperones

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Heat-shock proteins (hsps) have important roles in the development of the eye lens. We previously demonstrated that knockdown of hsp70 gene expression using morpholino antisense technology resulted in an altered lens phenotype in zebrafish embryos. A less severe phenotype was seen with knockdown of heat-shock factor 1 (HSF1), suggesting that, while it likely plays a role in hsp70 regulation during lens formation, other regulatory factors are also involved. Heatshock factor 4 plays an important role in mammalian lens development, and an expressed sequence tag encoding zebrafish HSF4 has been identified. The deduced amino acid sequence shares structural similarities with mammalian HSF4 including the lack of an HR-C domain. However, the HR-C domain is absent due to a severe C-terminal truncation within zebrafish HSF4 (zHSF4) relative to the mammalian protein. Surprisingly, the amino acid composition of the zHSF4 DNA binding domain shares a greater degree of identity with HSF1 proteins than it does with mammalian HSF4 proteins. Consistent with this, the binding affinity of in vitro synthesized zHSF4 for discontinuous heat-shock response element sequences is more limited, similar to what has been previously observed for HSF1 proteins. Hsf4 mRNA is expressed in zebrafish adult eye tissue but is only observed in developing embryonic tissue at 60 h post-fertilization or later. This, together with the lack of an observable phenotype following morpholino-based antisense knockdown of hsf4, suggests that zHSF4 is unlikely to play a role in regulating early embryonic lens development.

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A Homozygous Splice Mutation in theHSF4Gene Is Associated with an Autosomal Recessive Congenital Cataract

Abstract: This is the first report describing association of an autosomal recessive cataract with the HSF4 locus on 16q21-q22.1 and the first description of HSF4 splice variants in the lens showing that HSF4b is the major transcript.

Cited by 87 publications

References 21 publications

Congenital cataracts and their molecular genetics

Congenital cataracts and their molecular genetics

Clinical and experimental advances in congenital and paediatric cataracts

Zebrafish HSF4: a novel protein that shares features of both HSF1 and HSF4 of mammals

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