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Biomedical subjects

V van Heyningen

Publications and source records attributed to V van Heyningen.

At least 19 recordsLinked to original sources
PubMed2000

Hemolytic uremic syndrome associated with Denys-Drash syndrome.

The Denys-Drash syndrome is defined by the occurrence of combinations of pseudohermaphroditism, nephrotic syndrome with diffuse mesangial sclerosis, Wilms' tumor, and constitutional mutations in the WT1 suppressor gene. Most patients develop end-stage renal failure. Atypical hemolytic uremic syndrome (HUS) is defined by onset of acute hemolytic anemia with fragmented erythrocytes, thrombocytopenia, and renal failure in the absence of a gastrointestinal prodromal illness of bloody diarrhea. The purpose of this report is to describe the occurrence of features of atypical HUS and Denys-Drash syndrome in two African-American boys aged 13 and 16 months. Each had nephrotic syndrome, diffuse mesangial sclerosis, and WT1 point mutations. Both had grade III hypospadias and undescended testes. They had normal serum creatinine concentrations and hematology a month before presenting with HUS. Stool cultures for Escherichia coli O157:H7 were negative. Each patient has been transplanted with cadaver kidneys without recurrence of HUS.

Base Sequence↗
PubMed2000

Phenotypic variability and asymmetry of Rieger syndrome associated with PITX2 mutations.

PURPOSE: Rieger syndrome is an autosomal dominant condition characterized by a variable combination of anterior segment dysgenesis, dental anomalies, and umbilical hernia. To date, reports have shown mutations within the PITX2 gene associated with Rieger syndrome, iridogoniodysgenesis, and iris hypoplasia. The purposes of this study were to determine the range of expression and intrafamilial variability of PITX2 mutations in patients with anterior segment dysgenesis. METHODS: Seventy-six patients with different forms of anterior segment dysgenesis were classified clinically. DNA was obtained and screened by means of polymerase chain reaction (PCR)-single-stranded conformation polymorphism (SSCP) and heteroduplex analysis followed by direct sequencing. RESULTS: Eight of 76 patients had mutations within the PITX2 gene. Anterior segment phenotypes show wide variability and include a phenocopy of aniridia and Peters', Rieger, and Axenfeld anomalies. Mutations include premature terminations and splice-site and homeobox mutations, confirming that haploinsufficiency the likely pathogenic mechanism in the majority of cases. CONCLUSIONS: There is significant phenotypic variability in patients with PITX2 mutations, both within and between families. Developmental glaucoma is common. The umbilical and dental abnormalities are highly penetrant, define those at risk of carrying mutations in this gene, and guide mutation analysis. In addition, there is a range of other extraocular manifestations.

Anterior Eye Segment↗
PubMed1999

Multiple roles for the Wilms' tumor suppressor, WT1.

Wilms' tumor is a childhood kidney tumor that is a striking example of the way that cancer may arise through development gone awry. A proportion of these tumors develop as a result of the loss of function mutations in the Wilms' tumor suppressor gene, WT1. Inherited mutations in the WT1 gene can lead to childhood kidney cancer, severe gonadal dysplasia, and life-threatening hypertension. Knockouts show that the gene is essential for the early stages of kidney and gonad formation. These tissues are completely absent in null mice. The WT1 gene encodes numerous protein isoforms, all of which share four zinc fingers. There is a large body of evidence supporting the notion that WT1 is a transcription factor, particularly a transcriptional repressor. Recently, however, we obtained evidence that WT1 colocalizes and is physically associated with splice factors. What is more, one alternative splice isoform of WT1 containing three amino acids, Lys-Thr-Ser (KTS; inserted between zinc fingers 3 and 4) is preferentially associated with splice factors, whereas the other alternative splice version, lacking these three amino acids, preferentially associates with the transcriptional apparatus. Both genetic and evolutionary considerations suggest that these two different forms of the protein have different functions. We will discuss recent evidence to further implicate WT1 in splicing. Our results raise the possibility that regulation of splicing is a crucial factor in the development of the genitourinary system, and that tumors may arise through aberrant splicing. To pursue the regulation and function of WT1 in whole animals, we have been introducing the human gene and large flanking regions cloned in yeast artificial chromosomes directly into mice. These studies have allowed us to dissect the function of WT1 at late as well as at early stages in organogenesis and to identify new sites and surprising new potential functions for the gene.

Alternative Splicing↗
PubMed1999

EYA4, a novel vertebrate gene related to Drosophila eyes absent.

We have isolated a family of four vertebrate genes homologous to eyes absent (eya), a key regulator of ocular development in Drosophila. Here we present the detailed characterization of the EYA4 gene in human and mouse. EYA4 encodes a 640 amino acid protein containing a highly conserved C-terminal domain of 271 amino acids which in Drosophila eya is known to mediate developmentally important protein-protein interactions. Human EYA4 maps to 6q23 and mouse Eya4 maps to the predicted homology region near the centromere of chromosome 10. In the developing mouse embryo, Eya4 is expressed primarily in the craniofacial mesenchyme, the dermamyotome and the limb. On the basis of map position and expression pattern, EYA4 is a candidate for oculo-dento-digital (ODD) syndrome, but no EYA4 mutations were found in a panel of ODD patients.

Alternative Splicing↗
PubMed1999

Missense mutations in the most ancient residues of the PAX6 paired domain underlie a spectrum of human congenital eye malformations.

Mutations of the human PAX6 gene underlie aniridia (congenital absence of the iris), a rare dominant malformation of the eye. The spectrum of PAX6 mutations in aniridia patients is highly biased, with 92% of all reported mutations leading to premature truncation of the protein (nonsense, splicing, insertions and deletions) and just 2% leading to substitution of one amino acid by another (missense). The extraordinary conservation of the PAX6 protein at the amino acid level amongst vertebrates predicts that pathological missense mutations should in fact be common even though they are hardly ever seen in aniridia patients. This indicates that there is a heavy ascertainment bias in the selection of patients for PAX6 mutation analysis and that the 'missing' PAX6 missense mutations frequently may underlie phenotypes distinct from textbook aniridia. Here we present four novel PAX6 missense mutations, two in association with atypical phenotypes: ectopia pupillae (displaced pupils) and congenital nystagmus (searching gaze), and two in association with more recognizable aniridia phenotypes. Strikingly, all four mutations are located within the PAX6 paired domain and affect amino acids which are highly conserved in all known paired domain proteins. Our results support the hypothesis that the under-representation of missense mutations is caused by ascertainment bias and suggest that a substantial burden of PAX6 -related disease remains to be uncovered.

Amino Acid Sequence↗
PubMed1999

Psychiatric disorder and cognitive function in a family with an inherited novel mutation of the developmental control gene PAX6.

The PAX family of developmental control genes are known to play important roles in the early patterning of the central nervous system. One member of this family, PAX6, is involved in eye development in invertebrates as well as in mouse and man, but is also widely expressed in the developing forebrain. Humans with a mutation in this gene have abnormalities of eye development, and the results presented here suggest, for the first time, that this mutation may also be associated with subtle abnormalities of frontal lobe function in the family studied. We carried out genotyping of individuals within a single family, with and without the characteristic eye abnormalities of PAX6 mutation, and only those individuals with the mutation showed significant abnormalities on tests of frontal lobe function. These individuals also had higher rates of psychiatric disorder. PAX6 is highly conserved between mouse and man, and although the neuroanatomical phenotype associated with PAX6 heterozygosity has only been studied in mice, the resultant cellular disorganization seen in mice is likely to be present in the human forebrain. Although these mice have no obvious behavioural phenotype, the results presented here suggest that humans with the equivalent mutation display a neurobehavioural phenotype.

Adolescent↗
PubMed1999

Role of Pax6 in development of the cerebellar system.

Post-mitotic neurons generated at the rhombic lip undertake long distance migration to widely dispersed destinations, giving rise to cerebellar granule cells and the precerebellar nuclei. Here we show that Pax6, a key regulator in CNS and eye development, is strongly expressed in rhombic lip and in cells migrating away from it. Development of some structures derived from these cells is severely affected in Pax6-null Small eye (Pax6(Sey)/Pax6(Sey)) embryos. Cell proliferation and initial differentiation seem unaffected, but cell migration and neurite extension are disrupted in mutant embryos. Three of the five precerebellar nuclei fail to form correctly. In the cerebellum the pre-migratory granule cell sub-layer and fissures are absent. Some granule cells are found in ectopic positions in the inferior colliculus which may result from the complete absence of Unc5h3 expression in Pax6(Sey)/Pax6(Sey) granule cells. Our results suggest that Pax6 plays a strong role during hindbrain migration processes and at least part of its activity is mediated through regulation of the netrin receptor Unc5h3.

Animals↗
PubMed1998

Complete sequencing of the Fugu WAGR region from WT1 to PAX6: dramatic compaction and conservation of synteny with human chromosome 11p13.

The pufferfish Fugu rubripes has a genome approximately 7.5 times smaller than that of mammals but with a similar number of genes. Although conserved synteny has been demonstrated between pufferfish and mammals across some regions of the genome, there is some controversy as to what extent Fugu will be a useful model for the human genome, e.g., [Gilley, J., Armes, N. & Fried, M. (1997) Nature (London) 385, 305-306]. We report extensive conservation of synteny between a 1.5-Mb region of human chromosome 11 and <100 kb of the Fugu genome in three overlapping cosmids. Our findings support the idea that the majority of DNA in the region of human chromosome 11p13 is intergenic. Comparative analysis of three unrelated genes with quite different roles, WT1, RCN1, and PAX6, has revealed differences in their structural evolution. Whereas the human WT1 gene can generate 16 protein isoforms via a combination of alternative splicing, RNA editing, and alternative start site usage, our data predict that Fugu WT1 is capable of generating only two isoforms. This raises the question of the extent to which the evolution of WT1 isoforms is related to the evolution of the mammalian genitourinary system. In addition, this region of the Fugu genome shows a much greater overall compaction than usual but with significant noncoding homology observed at the PAX6 locus, implying that comparative genomics has identified regulatory elements associated with this gene.

Amino Acid Sequence↗
PubMed1998

The Human PAX6 Mutation Database.

The Human PAX6 Mutation Database contains details of 94 mutations of the PAX6 gene. A Microsoft Access program is used by the Curator to store, update and search the database entries. Mutations can be entered directly by the Curator, or imported from submissions made via the World Wide Web. The PAX6 Mutation Database web page at URL http://www.hgu.mrc.ac.uk/Softdata/PAX6/ provides information about PAX6, as well as a fill-in form through which new mutations can be submitted to the Curator. A search facility allows remote users to query the database. A plain text format file of the data can be downloaded via the World Wide Web. The Curation program contains prior knowledge of the genetic code and of the PAX6 gene including cDNA sequence, location of intron/exon boundaries, and protein domains, so that the minimum of information need be provided by the submitter or Curator.

Computer Communication Networks↗
PubMed1998

PAX6 mutations reviewed.

Mutations in PAX6 are responsible for human aniridia and have also been found in patients with Peter's anomaly, with congenital cataracts, with autosomal dominant keratitis, and with isolated foveal hypoplasia. No locus other than chromosome 11p13 has been implicated in aniridia, and PAX6 is clearly the major, if not only, gene responsible. Twenty-eight percent of identified PAX6 mutations are C-T changes at CpG dinucleotides, 20% are splicing errors, and more than 30% are deletion or insertion events. There is a noticeably elevated level of mutation in the paired domain compared with the rest of the gene. Increased mutation in the homeodomain is accounted for by the hypermutable CpG dinucleotide in codon 240. Very nearly all mutations appear to cause loss of function of the mutant allele, and more than 80% of exonic substitutions result in nonsense codons. In a gene with such extraordinarily high sequence conservation throughout evolution, there are presumed undiscovered missense mutations, these are hypothesized to exist in as-yet unidentified phenotypes.

Aniridia↗
PubMed1998

A new set of primers for mutation analysis of the human PAX6 gene.

Mutations in the human PAX6 gene are an important cause of dominantly inherited congenital malformations of the eye, including aniridia, Peters' anomaly, keratitis, and isolated foveal hypoplasia. To satisfy the need for efficient detection of PAX6 mutations, we have developed a new set of oligonucleotides for genomic SSCP based on the recently completed genomic sequence of the entire human PAX6 gene. We also describe PAX6 mutations in eight aniridia patients, five of which are novel.

Blood Cells↗
PubMed1998

In utero nephropathy, Denys-Drash syndrome and Potter phenotype.

We report an unusual case of Denys-Drash syndrome presenting in a newborn infant with end-stage renal failure of antenatal origin and Potter phenotype. DNA analysis showed a novel missense change in arginine 394 of zinc finger 3 of the WT1 gene. This mutation may lead to an earlier and more severe presentation of Denys-Drash syndrome. It may be of interest to look for this mutation in other Potter phenotype cases.

Abnormalities, Multiple↗
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↗