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Biomedical subjects

M A Walter

Publications and source records attributed to M A Walter.

At least 19 recordsLinked to original sources
PubMed1998

The forkhead/winged helix gene Mf1 is disrupted in the pleiotropic mouse mutation congenital hydrocephalus.

Mf1 encodes a forkhead/winged helix transcription factor expressed in many embryonic tissues, including prechondrogenic mesenchyme, periocular mesenchyme, meninges, endothelial cells, and kidney. Homozygous null Mf1lacZ mice die at birth with hydrocephalus, eye defects, and multiple skeletal abnormalities identical to those of the classical mutant, congenital hydrocephalus. We show that congenital hydrocephalus involves a point mutation in Mf1, generating a truncated protein lacking the DNA-binding domain. Mesenchyme cells from Mf1lacZ embryos differentiate poorly into cartilage in micromass culture and do not respond to added BMP2 and TGFbeta1. The differentiation of arachnoid cells in the mutant meninges is also abnormal. The human Mf1 homolog FREAC3 is a candidate gene for ocular dysgenesis and glaucoma mapping to chromosome 6p25-pter, and deletions of this region are associated with multiple developmental disorders, including hydrocephaly and eye defects.

Amino Acid Sequence↗
PubMed1998

Mutation in the RIEG1 gene in patients with iridogoniodysgenesis syndrome.

Axenfeld-Rieger syndrome (ARS) and iridogoniodysgenesis syndrome (IGDS) are clinically related autosomal dominant disorders which affect the anterior segment of the eye as well as non-ocular structures. ARS patients present with iris hypoplasia, a prominent Schwalbe line, adhesions between the iris stroma and the iridocorneal angle and increased intraocular pressure. IGDS is characterized by iris hypoplasia, goniodysgenesis and increased intraocular pressure. Each syndrome also presents with non-ocular features including maxillary hypoplasia, micro and anodontia, redundant periumbilical skin, hypospadius (in males), and each has been genetically linked to chromosome 4q25. RIEG1 , the gene responsible for the 4q25 ARS phenotype, recently has been cloned. RIEG1 encodes a novel member of the bicoid class of homeobox proteins known to be active as transcription factors. Mutational analysis has previously detected several mutations in this gene in ARS individuals. We have now detected a mutation in RIEG1 which segregates with the disease phenotype in a family with IGDS. This mutation is a G-->A transition altering an arginine residue to a histidine in a highly conserved location in the second helix of the homeobox of RIEG1. This mutation indicates that IGDS and ARS are allelic variants of the same disorder. This wide variability in clinical consequences of mutations at the RIEG1 4q25 locus implicates the RIEG gene broadly in ocular and craniofacial disorders.

Adolescent↗
PubMed1997

Identification of the human chromosomal region containing the iridogoniodysgenesis anomaly locus by genomic-mismatch scanning.

Genome-mismatch scanning (GMS) is a new method of linkage analysis that rapidly isolates regions of identity between two genomes. DNA molecules from regions of identity by descent from two relatives are isolated based on their ability to form extended mismatch-free heteroduplexes. We have applied this rapid technology to identify the chromosomal region shared by two fifth-degree cousins with autosomal dominant iridogoniodysgenesis anomaly (IGDA), a rare ocular neurocristopathy. Markers on the short arm of human chromosome 6p were recovered, consistent with the results of conventional linkage analysis conducted in parallel, indicating linkage of IGDA to 6p25. Control markers tested on a second human chromosome were not recovered. A GMS error rate of approximately 11% was observed, well within an acceptable range for a rapid, first screening approach, especially since GMS results would be confirmed by family analysis with selected markers from the putative region of identity by descent. These results demonstrate not only the value of this technique in the rapid mapping of human genetic traits, but the first application of GMS to a multicellular organism.

Chromosome Mapping↗
PubMed1996

A high-resolution whole genome radiation hybrid map of human chromosome 17q22-q25.3 across the genes for GH and TK.

We have constructed a whole genome radiation hybrid (WG-RH) map across a region of human chromosome 17q, from growth hormone (GH) to thymidine kinase (TK). A panel of 128 WG-RH hybrid cell lines generated by X-irradiation and fusion has been tested for the retention of 39 sequence-tagged site (STS) markers by the polymerase chain reaction. This genome mapping technique has allowed the integration of existing VNTR and microsatellite markers with additional new markers and existing STS markers previously mapped to this region by other means. The WG-RH map includes eight expressed sequence tag (EST) and three anonymous markers developed for this study, together with 23 anonymous microsatellites and five existing ESTs. Analysis of these data resulted in a high-density comprehensive map across this region of the genome. A subset of these markers has been used to produce a framework map consisting of 20 loci ordered with odds greater than 1000:1. The markers are of sufficient density to build a YAC contig across this region based on marker content. We have developed sequence tags for both ends of a 2.1-Mb YAC and mapped these using the WG-RH panel, allowing a direct comparison of cRay6000 to physical distance.

Animals↗
PubMed1996

Fibroblast growth factor-induced motor end plate regeneration in atrophic muscle.

OBJECTIVE: To determine whether fibroblast growth factor 1 implanted with viable nerve into atrophic muscle will stimulate formation of functional, acetylcholine producing motor end plates. DESIGN: Twelve male Lewis rats underwent predenervation of the hamstring muscle 8 weeks before implantation of the nerve at a site distant from the original motor end plate. Six animals underwent implantation of the tagged nerve ending into atrophic muscle with 50 microgram of fibroblast growth factor 1 in a fibrin adhesive carrier (group 1). Three animals underwent implantation with nerve, fibrin adhesive, and no fibroblast growth factor 1 (group 2); and three animals underwent implantation with fibroblast growth factor 1 and fibrin adhesive with no nerve (group 3). Animals were killed 9 weeks after implantation and nerve and muscle specimens were harvested. MAIN OUTCOME MEASURES: Histoenzymologic methods for acetylcholinesterase and silver impregnation of nerve fibers were performed 9 weeks after fibroblast growth factor 1-fibrin adhesive implantation. Variables included the number of motor end plates per highpower field and motor end plate length. RESULTS: Robust axonal sprouting and formation of multiple motor end plates were found arborized in serial fashion equidistant around the implanted nerve ending. Rare extrasynaptic staining occurred. End plate lengths were significantly shorter in the fibroblast growth factor 1-treated muscles (group 1) than in the specimens without fibroblast growth factor 1 (group 2) (31.2 vs 58.5 micron; P>001, paired t test). The arborization of motor end plates, rare extrasynaptic staining, and shorter end plate lengths seen in group 1 were all consistent with mature motor end plates. Controls (group 3) displayed limited motor end plate formation and extensive extrasynaptic staining typical of denervation. CONCLUSION: This study presents encouraging evidence that fibroblast growth factor 1 with fibrin adhesive carrier can facilitate the reinnervation of atrophied muscle by enhancing the formation or revitalization of motor end plates. Future studies will address muscle function and use of different carrier materials.

Animals↗
PubMed1996

Autosomal-dominant iridogoniodysgenesis and Axenfeld-Rieger syndrome are genetically distinct.

PURPOSE: To determine whether there is a locus for iridogoniodysgenesis (IGD)/ familial iris hypoplasia in the region of the known Axenfeld-Rieger syndrome (ARS) locus at 4q25 and to determine the ocular phenotype within the autosomal-dominant iris hypoplasia group of disorders. METHODS: Clinical examinations were performed on 27 members, with 11 affected from one family in which the IGD occurred in association with the nonocular features of ARS, and on 70 members with 30 affected from a second IGD family with ocular features only. Family members were genotyped for markers within the 4q25 region known to contain a locus for ARS. LOD scores were calculated with the MLINK option of the LINKAGE program. RESULTS: The iris hypoplasia in each IGD family was similar. In the IGD family with only ocular features (IGD anomaly), however, a majority of those affected had a goniodysgenesis with excess tissue in the angle and anomalous angle vascularity. These findings were absent in the IGD family with syndromic features (IGD syndrome). Linkage to the 4q25 region was excluded in the IGD anomaly family, whereas the family with IGD syndrome was found to be completely linked to the 4q25 region (peak LOD score with D4S407 of 7.827 at theta = 0.00). CONCLUSIONS: The authors' results suggest that mutations at the 4q25 locus can result in variable ocular features that also occur in combination with nonocular (dental and jaw) anomalies. Mutation of a separate locus must underlie IGD with ocular features only. A re-evaluation of the relation between the various forms of autosomal-dominant iris hypoplasia, therefore, may be warranted.

Abnormalities, Multiple↗
PubMed1996

A high-resolution radiation hybrid map of the region surrounding the Gorlin syndrome gene.

We have constructed a set of hybrid cell lines by irradiation of GM 64063 (human chromosome 9q only on hamster background) and fusion to hamster A23 Tk-, 109 independent lines were tested by PCR with 24 markers from chromosome 9q. The marker density is highest in the 9q22.3-q31 region containing the gene for Gorlin syndrome, a familial predisposition to basal cell carcinoma. The resolution of our map in this region is significantly higher than other published maps and will enable accurate placing of new markers and genes within the 9q22.3-q3.1 region. This is important since yeast artificial chromosomes from the region are likely to contain deletions.

Animals↗
PubMed1996

SOX genes: architects of development.

Development in higher organisms involves complex genetic regulation at the molecular level. The emerging picture of development control includes several families of master regulatory genes which can affect the expression of down-stream target genes in developmental cascade pathways. One new family of such development regulators is the SOX gene family. The SOX genes are named for a shared motif called the SRY box a region homologous to the DNA-binding domain of SRY, the mammalian sex determining gene. Like SRY, SOX genes play important roles in chordate development. At least a dozen human SOX genes have been identified and partially characterized (Tables 1 and 2). Mutations in SOX9 have recently been linked to campomelic dysplasia and autosomal sex reversal, and other SOX genes may also be associated with human disease.

Amino Acid Sequence↗
PubMed1996

Autosomal dominant iridogoniodysgenesis anomaly maps to 6p25.

Autosomal dominant iridogoniodysgenesis anomaly (IGDA) is characterized by iris hypoplasia and goniodysgenesis with frequent juvenile glaucoma. IGDA is the result of aberrant migration or terminal induction of the neural crest cells involved in the formation of the anterior chamber of the eye. After eliminating candidate regions for other ocular disorders, a genome-wide scan for IGDA was performed using linkage analysis. Approximately 95% of the genome was excluded with >300 microsatellite markers before significant linkage was demonstrated between IGDA and chromosome 6 markers in two families. From haplotype analysis and identification of recombinants, the IGDA locus is mapped to an 8.3-cM interval distal to D6S477, at 6p25. Our linkage results are consistent with the ocular findings in rare cases of individuals with chromosomal anomalies involving deletions of 6p. This suggests that there is a major gene involved in eye anterior segment development at 6p25.

Chromosome Mapping↗
PubMed1995

Irradiation and fusion gene transfer.

Irradiation and fusion gene transfer (IFGT) is a technique that spans the gap between the limitations of molecular methods and somatic-cell genetics, allowing the separation of DNA fragments between 0.25 and 30 Mb in size. In conjunction with genetic linkage analysis and physical mapping techniques, IFGT provides a very useful addition to methods for cloning disease loci, and mapping chromosomes and entire genomes.

Animals↗
PubMed1995

Mutation of the PAX6 gene in patients with autosomal dominant keratitis.

Autosomal dominant keratitis (ADK) is an eye disorder chiefly characterized by corneal opacification and vascularization and by foveal hypoplasia. Aniridia (shown recently to result from mutations in the PAX6 gene) has overlapping clinical findings and a similar pattern of inheritance with ADK. On the basis of these similarities, we used a candidate-gene approach to investigate whether mutations in the PAX6 gene also result in ADK. Significant linkage was found between two polymorphic loci in the PAX6 region and ADK in a family with 15 affected members in four generations (peak LOD score = 4.45; theta = .00 with D11S914), consistent with PAX6 mutations being responsible for ADK. SSCP analysis and direct sequencing revealed a mutation in the PAX6 exon 11 splice-acceptor site. The predicted consequent incorrect splicing results in truncation of the PAX6 proline-serine-threonine activation domain. The SeyNeu mouse results from a mutation in the Pax-6 exon 10 splice-donor site that produces a PAX6 protein truncated from the same point as occurs in our family with ADK. Therefore, the SeyNeu mouse is an excellent animal model of ADK. The finding that mutations in PAX6 underlie ADK, along with a recent report that mutations in PAX6 also underlie Peters anomaly, implicates PAX6 broadly in human anterior segment malformations.

DNA-Binding Proteins↗
PubMed1994

The immunoglobulin heavy chain and disease association: application to pemphigus vulgaris.

Genes involved in the immune response are generally encoded from a complex cluster of gene segments. Studies of the association of diseases with such genes require well-defined genetic markers throughout the selected region. A set of 15 polymorphic loci that span 1500 kb of the immunoglobulin heavy chain (IGH) complex, 8 in the variable (VH) region and 7 in the constant (CH) region, were selected for the study of disease association. We present a protocol for the use of multiple immunoglobulin heavy chain (IGH) polymorphisms for general application in disease association studies. No microsatellite repeat markers are available for this region. To demonstrate the applicability of this approach, we have examined these IGH polymorphisms in families with individuals affected with pemphigus vulgaris (PV), an autoimmune dermatologic disease. Allele frequencies in 12 patients with PV were compared with those found in their spouses, and with those in a white Canadian control population. A significant difference was found between PV patients and both control groups for the presence of the VH gene VH3f-R4, and possibly for the absence of VH3f-R3, suggesting the possibility of susceptibility factors in these regions. Examination of the frequencies of the IGH region C gamma-haplotypes of PV patients indicated that, while the patients did not differ significantly from their spouses (chi 2 = 1.79), both groups were found to differ significantly from the white Canadian control group (chi 2 = 10.10), emphasizing the importance of matching the ethnic background of controls with that of the patient test group in disease association studies. Unexpectedly, two patients had large deletions of genes in the IGH constant region, which could play a role in the development of PV and require further investigation.

Alleles↗
PubMed1994

A method for constructing radiation hybrid maps of whole genomes.

In radiation hybrid mapping, chromosomes in human-rodent hybrid cells are fragmented by X-rays and fragments rescued by fusion of the donor cell to a recipient rodent cell. The co-retention frequencies of markers in 100-200 hybrids are used to map individual chromosomes, but mapping the whole genome in this way is impractical. We have reverted to the original protocols of Goss and Harris and have produced a panel of 44 hybrids using irradiated human fibroblasts as donors. This panel has been used to make a map of human chromosome 14 containing 40 ordered markers. The map integrates previously published maps and localizes nine new markers. We suggest that the construction of a high resolution map of the whole human genome is feasible with a single panel of 100-200 hybrids.

Animals↗
PubMed1993

Immunoglobulin heavy chain variable region polymorphisms and multiple sclerosis susceptibility.

In addition to the major histocompatibility complex (MHC), genetic susceptibility in multiple sclerosis (MS) appears to be influenced by other loci. A recent study has identified a population association with an immunoglobulin heavy chain variable region polymorphism in the VH2-B5 family, with both familial and sporadic MS patients. We have repeated this association study in a second MS patient group and used two ethnically and geographically matched control groups and the MS patients' unaffected sibs for comparisons. The VH2-B5 polymorphism was found to be over-represented in MS patients when compared to all three control groups. This VH2-B5 association was stronger when the MS patient data were combined with data from our previous study. To further explore the implications of this population association, MS sibships were analyzed for haplotype sharing by identity by descent (IBD) for VH2 and VH3f gene segment polymorphisms. The distribution of haplotype sharing did not differ from that expected based upon random segregation. The data are consistent with the IGVH locus exerting a minor effect perhaps by interacting with other loci to influence MS susceptibility or with genetic heterogeneity and a role for this complex in a subgroup of patients.

Alleles↗