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V van Heyningen

Publications and source records attributed to V van Heyningen.

At least 37 records · Page 2Linked to original sources
PubMed1998

Position effect in human genetic disease.

The spatially, temporally and quantitatively correct expression of a gene requires the presence not only of intact coding sequence, free of adverse nucleotide changes, but also correctly functioning regulatory control. With the identification of an increasing number of disease-related genes, the molecular defect in many cases has been defined. It is becoming clear that it is not always the transcription unit that bears the defect: there are a number of cases where the regulation of gene expression has been compromised. Cases associated with chromosomal rearrangement outside the transcription and promoter regions are categorized as position effects. A number of different mechanisms may explain their aetiology. Here, we examine the human disorders where such position effects are implicated. Further study of such cases may lead to important insights into mechanisms of gene regulation and transcriptional control.

Animals↗
PubMed1997

Tandem duplication of 11p12-p13 in a child with borderline development delay and eye abnormalities: dose effect of the PAX6 gene product?

We report on a girl with a duplication of chromosome band 11p12-->13, which includes the Wilms tumor gene (WT1) and the aniridia gene (PAX6). The girl had borderline developmental delay, mild facial anomalies, and eye abnormalities. Eye findings were also present in most of the 11 other published cases with partial trisomy 11p, including 11p12-->13. Recently, it was shown that introduction of additional copies of the PAX6 gene into mice caused very variable eye abnormalities. Therefore, a PAX6 gene dosage effect is likely to be present in mice and humans. The central nervous system may be less sensitive to an altered PAX6 gene dosage, which is consistent with the borderline developmental delay in the present patient. Urogenital abnormalities were absent in this patient and in most of the other patients with partial trisomy of 11p. Therefore, the effect of a WT1 gene duplication on the embryological development of the urogenital tract remains uncertain.

Chromosome Aberrations↗
PubMed1997

Pax6 controls progenitor cell identity and neuronal fate in response to graded Shh signaling.

Distinct classes of motor neurons and ventral interneurons are generated by the graded signaling activity of Sonic hedgehog (Shh). Shh controls neuronal fate by establishing different progenitor cell populations in the ventral neural tube that are defined by the expression of Pax6 and Nkx2.2. Pax6 establishes distinct ventral progenitor cell populations and controls the identity of motor neurons and ventral interneurons, mediating graded Shh signaling in the ventral spinal cord and hindbrain.

Animals↗
PubMed1997

The reticulocalbin gene maps to the WAGR region in human and to the Small eye Harwell deletion in mouse.

We describe the localization of the gene encoding reticulocalbin, a Ca2+-binding protein of the endoplasmic reticulum, on human chromosome 11p13 midway between the WT1 and the PAX6 genes and show that it is hemizygously deleted in WAGR individuals. The mouse reticulocalbin gene is also shown to map to the region of conserved synteny on mouse chromosome 2 and to be deleted in the Small eye Harwell (SeyH) mutation. Loss of the reticulocalbin gene could contribute to the early lethality of SeyH and SeyDey homozygotes.

Abnormalities, Multiple↗
PubMed1997

Combined SSCP/heteroduplex analysis in the screening for PAX6 mutations.

We demonstrate the use of combined SSCP and heteroduplex analysis in the detection of PAX6 mutations using non-radioactive silver staining. A panel of aniridia patients was screened by this approach and we show that a greater number of mutations was detected than would have been found by running each technique alone. Six previously unreported aniridia mutations in PAX6 are also described..

Aniridia↗
PubMed1997

A FISH approach to defining the extent and possible clinical significance of deletions at the WAGR locus.

Nineteen patients were analysed by fluorescence in situ hybridisation (FISH) with selected 11p13 markers. They were examined because they had either isolated sporadic or familial aniridia, or aniridia with one or more of the WAGR (Wilms' tumour, aniridia, genital anomalies, and mental retardation) syndrome anomalies. The FISH markers from distal 11p13 were cosmids FO2121, PAX6 (aniridia), D11S324, and WT1 (Wilms' tumour predisposition). Two of the patients with isolated aniridia were abnormal, one with an apparently balanced reciprocal 7;11 translocation and an 11p13 breakpoint, which by FISH was shown to be approximately 30 kb distal to the aniridia (PAX6) gene, and the other had a submicroscopic deletion involving part of PAX6 that extended distally for approximately 245 kb. Two patients with aniridia together with other WAGR malformations had deletions involving all four cosmids. One case with aniridia associated with developmental and growth delay had a deletion including FO2121 and PAX6 but not D11S324 and WT1, while in a further case the deletion included all four test cosmids. These studies show that a combined conventional and molecular cytogenetic approach to patients presenting with aniridia is a useful method for differentiating between those with deletions extending into and including WT1 and therefore between those with high and low risks of developing Wilms' tumour.

Aniridia↗
PubMed1997

The incidence of PAX6 mutation in patients with simple aniridia: an evaluation of mutation detection in 12 cases.

Twelve aniridia patients, five with a family history and seven presumed to be sporadic, were exhaustively screened in order to test what proportion of people with aniridia, uncomplicated by associated anomalies, carry mutations in the human PAX6 gene. Mutations were detected in 90% of the cases. Three mutation detection techniques were used to determine if one method was superior for this gene. The protein truncation test (PTT) was used on RT-PCR products, SSCP on genomic PCR amplifications, and chemical cleavage of mismatch on both RT-PCR and genomic amplifications. For RT-PCR products, only the translated portion of the gene was screened. On genomic products exons 1 to 13 (including 740 bp of the 3' untranslated sequence and all intron/exon boundaries) were screened, as was a neuroretina specific enhancer in intron 4. Ten of the possible 12 mutations in the five familial cases and five of the sporadic patients were found, all of which conformed to a functional outcome of haploinsufficiency. Five were splice site mutations (one in the donor site of intron 4, two in the donor site of intron 6, one in each of the acceptor sites of introns 8 and 9) and five were nonsense mutations in exons 8, 9, 10, 11, and 12. SSCP analysis of individually amplified exons, with which nine of the 10 mutations were seen, was the most useful detection method for PAX6.

Aniridia↗
PubMed1996

Influence of PAX6 gene dosage on development: overexpression causes severe eye abnormalities.

Aniridia in man and Small eye in mice are semidominant developmental disorders caused by mutations within the paired box gene PAX6. Whereas heterozygotes suffer from iris hypoplasia, homozygous mice lack eyes and nasal cavities and exhibit brain abnormalities. To investigate the role of gene dosage in more detail, we have generated yeast artificial chromosome transgenic mice carrying the human PAX6 locus. When crossed onto the Small eye background, the transgene rescues the mutant phenotype. Strikingly, mice carrying multiple copies on a wild-type background show specific developmental abnormalities of the eye, but not of other tissues expressing the gene. Thus, at least five different eye phenotypes are associated with changes in PAX6 expression. We provide evidence that not only reduced, but also increased levels of transcriptional regulators can cause developmental defects.

Animals↗
PubMed1996

EagI and NotI linking clones from human chromosomes 11 and Xp.

EagI and NotI linking libraries were prepared in the lambda vector, EMBL5, from the mouse-human somatic cell hybrid 1W1LA4.9, which contains human chromosomes 11 and Xp as the only human component. Individual clones containing human DNA were isolated by their ability to hybridise with total human DNA and digested with SalI and EcoRI to identify the human insert size and single-copy fragments. The mean (+/- SD) insert sizes of the EagI and NotI clones were 18.3 +/- 3.2 kb and 16.6 +/- 3.6 kb, respectively. Regional localisation of 66 clones (52 EagI, 14 NotI) was achieved using a panel of 20 somatic cell hybrids that contained different overlapping deletions of chromosomes 11 or Xp. Thirty-nine clones (36 EagI, 3 NotI) were localised to chromosome 11; 17 of these were clustered in 11q13 and another nine were clustered in 11q14-q23.1. Twenty-seven clones (16 EagI, 11 NotI) were localised to Xp and 10 of these were clustered in Xp11. The 66 clones were assessed for seven different microsatellite repetitive sequences; restriction fragment length polymorphisms for five clones from 11q13 were also identified. These EagI and NotI clones, which supplement those previously mapped to chromosome 11 and Xp, should facilitate the generation of more detailed maps and the identification of genes that are associated with CpG-rich islands.

Animals↗
PubMed1996

Transcription factors in disease.

Mutations affecting several predominantly tissue-specific transcriptional regulators have recently been associated with disease phenotypes. Although the mutational spectrum is variable, many of the reported cases involve clear loss-of-function mutations-such as Waardenburg syndrome type 1, aniridia and Rubinstein-Taybi syndrome-suggesting that the genetic mechanism involved in disease is haplo-insufficiency. The high degree of dosage sensitivity often appears to affect only a subset of the tissues that express the gene. Position effects with cytogenetic rearrangements well outside the coding region have been implicated for four of the genes discussed: POU3F4, SOX9, PAX6, and GL13.

Animals↗
PubMed1995

The evolution of WT1 sequence and expression pattern in the vertebrates.

WT1 is a Wilms' tumour predisposition gene, encoding a protein with four C-terminal Kruppel-type zinc fingers, which is also a major regulator of kidney and gonadal development. To pinpoint key regulatory domains involved in development and evolution of the vertebrate genitourinary system, we have isolated WT1 orthologues from all gnathostome classes. Partial nucleotide sequence from chick, alligator, Xenopus laevis and zebrafish reveals extensive conservation. Both the zinc fingers and the transregulatory domain exhibit a high level of similarity in all the species examined. However, of the two alternatively spliced regions only one, the three amino acid KTS insertion between zinc fingers 3 and 4, is found in species other than mammals. The 17 amino acid insertion at the C-terminal end of the transregulatory domain is present only in mammals. Residues with reported human pathological mutations are also unaltered across species, underlining their structural significance. Studies in chick and alligator reveal that the mammalian intermediate mesoderm expression pattern is conserved in birds and reptiles. A wider role in mesodermal differentiation is suggested by expression in some paraxial and lateral mesoderm derivatives.

Alligators and Crocodiles↗
PubMed1995

Subnuclear localization of WT1 in splicing or transcription factor domains is regulated by alternative splicing.

WT1 is a tumor suppressor gene with a key role in urogenital development and the pathogenesis of Wilms' tumor. Two alternative splice sites in the WT1 transcript allow the gene to encode four proteins. These carry four Krüppel-type zinc fingers and to date have primarily been implicated in transcriptional control of genes involved in growth regulation. However, here we demonstrate colocalization of WT1 with splicing factors in the fetal kidney and testis and in expressing cell lines. Using immunoprecipitation, we show that two WT1 isoforms directly associate with one or a limited number of components in the spliceosomes and coiled bodies. Moreover, COS cell expression studies suggest that alternative splicing within the WT1 zinc finger region determines whether the protein localizes mainly with splicing factors or with DNA in transcription factor domains in the nucleus. We propose that WT1 plays roles in posttranscriptional processing of RNA as well as in transcription.

Alternative Splicing↗