Mutant DNA-binding domain of HSF4 is associated with autosomal dominant lamellar and Marner cataract

Bu, Lei; Jin, Yiping; Shi, Yuefeng; Chu, Ren-yuan; Ban, Airong; Eiberg, Hans; Andres, Lisa; Jiang, Hongzhi; Zheng, Guangyong; Qian, Meiqian; Cui, Bin; Xia, Yu; Liu, Jing; Hu, Landian; Zhao, Guoping; Hayden, Michael R.; Kong, Xiangyin

doi:10.1038/ng921

Cited by 205 publications

(146 citation statements)

References 18 publications

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“…5 and 6), it is also possible that these transcription factors may be inactive at this stage. Second, mutations in HSF4 have been recently reported to be associated with the most prevalent form of early childhood cataracts (lamellar cataracts) (19). The almost exclusive expression of HSF4 in the postnatal ocular lens reported here corresponds remarkably to the timing of the appearance of this disease phenotype (juvenile cataractogenesis).…”

Section: Fig 5 Hse-␣b/hsf Complexes Contain Hsf4mentioning

confidence: 61%

“…Coupled with the demonstration that HSF4 and not HSF1 can be detected in the adult human lens extracts (Fig. 4), these data also provide a molecular basis for the association of late-onset cataract, such as Marner's cataract, with a mutation in the HSF4 DNA binding domain (19). How these mutations alter HSF4 DNA binding abilities remains to be investigated.…”

Section: Fig 5 Hse-␣b/hsf Complexes Contain Hsf4mentioning

confidence: 94%

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Developmentally Dictated Expression of Heat Shock Factors: Exclusive Expression of HSF4 in the Postnatal Lens and Its Specific Interaction with αB-crystallin Heat Shock Promoter

Somasundaram¹,

Bhat

2004

Journal of Biological Chemistry

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The molecular cascade of stress response in higher eukaryotes commences in the cytoplasm with the trimerization of the heat shock factor 1 (HSF1), followed by its transport to the nucleus, where it binds to the heat shock element leading to the activation of transcription from the down-stream gene(s). This well-established paradigm has been mostly studied in cultured cells. The developmental and tissue-specific control of the heat shock transcription factors (HSFs) and their interactions with heat shock promoters remain unexplored. We report here that in the rat lens, among the three mammalian HSFs, expression of HSF1 and HSF2 is largely fetal, whereas the expression of HSF4 is predominantly postnatal. Similar pattern of expression of HSF1 and HSF4 is seen in fetal and adult human lenses. This stagespecific inverse relationship between the expression of HSF1/2 and HSF4 suggests tissue-specific management of stress depending on the presence or absence of specific HSF(s). In addition to real-time PCR and immunoblotting, gel mobility shift assays, coupled with specific antibodies and HSE probes, derived from three different heat shock promoters, establish that there is no HSF1 or HSF2 binding activity in the postnatal lens nuclear extracts. Using this unique, developmentally modulated in vivo system, we demonstrate 1) specific patterns of HSF4 binding to heat shock elements derived from ␣B-crystallin, Hsp70, and Hsp82 promoters and 2) that it is HSF4 and not HSF1 or HSF2 that interacts with the canonical heat shock element of the ␣B-crystallin gene.Induced transcription from heat shock promoters is mediated by the activation of transacting HSFs 1 (1, 2). There are four known HSFs (HSF1, HSF2, HSF3, and HSF4). HSF3 is an avian HSF (3, 4). Although yeast and Drosophila melanogaster have a single gene that encodes an HSF, higher eukaryotes, animals, and plants have multiple genes that code for HSFs (4 -6). HSF1 and HSF2 transcription factors have almost identical gene structures (4). The heat shock response starts with the cytoplasmic HSF and its trimerization and transport to the nucleus, where it binds to the heat shock element (HSE) in the heat shock promoter, activating transcription of the down stream heat shock gene(s) (1, 4). Both HSF1 and HSF2 contain three hydrophobic repeats, HR-A, -B, and -C. HR-A and -B are involved in trimerization upon reception of the stress signal. HR-C, located at the carboxyl terminus, has been suggested to inhibit trimerization in the uninduced state. HSF4, on the other hand, does not contain the HR-C domain; it therefore exists as a trimeric unit and binds to the DNA constitutively (for review, see Ref. 4).HSF1 is considered to be the universal HSF and mediates expression of heat shock genes upon reception of a stress signal such as high temperature, whereas HSF2 is associated with developmental control. Although it has not been experimentally established, the assumption in this generalization is that all tissues and cells contain HSF1 as a pre-existing HSF in the cytoplasm to enab...

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Section: Fig 5 Hse-␣b/hsf Complexes Contain Hsf4mentioning

confidence: 61%

Section: Fig 5 Hse-␣b/hsf Complexes Contain Hsf4mentioning

confidence: 94%

Developmentally Dictated Expression of Heat Shock Factors: Exclusive Expression of HSF4 in the Postnatal Lens and Its Specific Interaction with αB-crystallin Heat Shock Promoter

Somasundaram¹,

Bhat

2004

Journal of Biological Chemistry

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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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“…23 -26 In addition, five genes for lens membrane/cytoskeletal proteins includ-ing those for connexin50 (GJA8) on 1q, 27 -29 connexin46 (GJA3) on 13q, 30,31 aquaporin-0 (MIP) on 12q, 32 a peripheral myelin-like protein (LIM2) on 19q 33 and an intermediate filament-like protein (BFSP2) on 3q 34,35 have been linked with Mendelian cataract. Moreover, certain mutations in genes widely expressed outside the lens, including those for paired-like homeodomain transcription factor 3 (PITX3) on 10q, 36 heat-shock transcription factor 4 (HSF4) on 16q, 37 galactokinase 1 (GALK1) on 17q 38 and L-ferritin (FTL) on 19q, 39 have been associated with cataract in the absence of other significant ocular or systemic defects. To gain further insight about the pathogenetic complexity of hereditary cataract, we have carried out linkage analysis in a family segregating autosomal dominant 'nuclear' cataract and subsequently identified a novel missense mutation in the gene for alphaA-crystallin (CRYAA) on 21q, which encodes a member of the small-heat-shock protein (sHSP) family of molecular chaperones.…”

Section: Introductionmentioning

confidence: 99%

Cell death triggered by a novel mutation in the alphaA-crystallin gene underlies autosomal dominant cataract linked to chromosome 21q

2003

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Hereditary cataract is a clinically and genetically heterogeneous lens disease that accounts for a significant proportion of visual impairment and blindness in childhood. The alphaA-crystallin (CRYAA) gene (CRYAA) encodes a member of the small-heat-shock protein (sHSP) family of molecular chaperones and is primarily and abundantly expressed in the ocular lens. Here, we have used linkage analysis to identify a novel missense mutation in CRYAA that underlies an autosomal dominant form of 'nuclear' cataract segregating in a four-generation Caucasian family. A maximum two-point LOD score (Z max ) of 2.19 (maximum recombination fraction, h max ¼ 0) and multipoint Z max of 3.3 (h max ¼ 0) was obtained at marker D21S1885. Haplotype analysis indicated that the disease gene lay in the B2.7 Mb physical interval between D21S1912 and D21S1260 flanking CRYAA on 21q22.3. Sequence analysis identified a C-T transition in exon 1 of CRYAA from affected individuals that was predicted to result in the nonconservative substitution of cysteine for arginine at codon 49 (R49C). Transfection studies of lens epithelial cells revealed that, unlike wild-type CRYAA, the R49C mutant protein was abnormally localized to the nucleus and failed to protect from staurosporine-induced apoptotic cell death. This study has identified the first dominant cataract mutation in CRYAA located outside the phylogenetically conserved 'alpha-crystallin core domain' of the sHSP family.

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Mutant DNA-binding domain of HSF4 is associated with autosomal dominant lamellar and Marner cataract

Cited by 205 publications

References 18 publications

Developmentally Dictated Expression of Heat Shock Factors: Exclusive Expression of HSF4 in the Postnatal Lens and Its Specific Interaction with αB-crystallin Heat Shock Promoter

Developmentally Dictated Expression of Heat Shock Factors: Exclusive Expression of HSF4 in the Postnatal Lens and Its Specific Interaction with αB-crystallin Heat Shock Promoter

Clinical and experimental advances in congenital and paediatric cataracts

Cell death triggered by a novel mutation in the alphaA-crystallin gene underlies autosomal dominant cataract linked to chromosome 21q

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