No description available.

Thesis (M.P.H.)--University of Hong Kong, 2009. / Includes bibliographical references (p. 36-39).

Thesis (Ph. D.)--University of Texas at Austin, 2001. / Vita. Includes bibliographical references. Available also from UMI/Dissertation Abstracts International.

Several investigators have suggested that "upper" neural tube defects (NTD's)--anencephaly, encephalocele, and thoracic spina bifida--are etiologically different from "lower" NTD's (lumbo-sacral spina bifida). This hypothesis was primarily based on the observations that the two types have different sex ratios and recurrence rates and that the NTD cases within one sibship are concordant for NTD type. In order to test this, the above figures were calculated in a sample of NTD probands from Montreal and Newfoundland. The findings were not consistent with the hypothesis. However, a previously unreported finding was observed: the frequency of twinning was significantly higher in the near relatives of upper NTD probands than in those of lower NTD probands or of controls. This curious association between upper NTD's and twinning may be explained by a familial factor predisposing to a delay early in development. This delay could also explain any differences observed in upper and lower NTD groups.

Source: Dissertation Abstracts International, Volume: 70-03, Section: B, page: 1623. Adviser: Ross Shegog. Includes bibliographical references.

published_or_final_version / Community Medicine / Master / Master of Public Health

No description available.

Not available / text

Splotch (Sp) is a semidominant mouse mutant which maps to the proximal portion of chromosome 1 and is phenotypically expressed as a pleiotropic defect during neurogenesis, resulting in spina bifida, exencephaly and dysgenesis of neural crest cell derivatives. To identify the aberrant gene underlying the defects observed in the Sp mouse mutant we initiated positional cloning strategy. Our preliminary efforts were directed at establishing the boundaries of a deleted chromosomal segment found in the Sp$ sp{r}$ allele, using nine gene probes that were assigned to that region of chromosome 1. Four of these genes, Vil, Des, Inha, and Akp-3, spanning a genetic distance of approximately 15 cM, were found to map within the Sp$ sp{r}$ deletion. In order to further delineate the subchromosomal location of the Sp gene, the proximal segment of mouse chromosome 1 was saturated with microclones isolated from a library of microdissected genomic fragments generated from this region. An additional eight markers were found to map within the confines of the Sp$ sp{r}$ deletion. / During the course of this work a member of the paired box gene family, Pax-3, was described as a candidate for Sp. The striking similarity between the tissue distribution of Pax-3 mRNA in normal developing embryos, and the neural structures affected in Sp mice, together with the chromosome 1 location of Pax-3 led us to examine whether Pax-3 was mutated in three alleles at this locus Sp$ sp{r}$, Sp$ sp{2H}$ and Sp. The entire Pax-3 gene was determined to be deleted in the Sp$ sp{r}$ allele. Analysis of genomic DNA and cDNA clones constructed from RNA isolated from $Sp sp{2H}/Sp sp{2H}$ embryos identified a deletion of 32 nucleotides within the paired type homeobox and is predicted to produce a truncated protein as a result of a newly created termination codon at the deletion breakpoint. The original Sp allele was also characterized and found to contain an A to T transversion at position -2 in the third intron of Pax-3 which abrogates the normal splicing of this intron due to the loss of its natural 3$ sp prime$ splice acceptor. Taken together, these studies indicate that the severe defect in neural tube formation detected in Sp and its allelic variants is linked to the inactivation of the paired box gene Pax-3, and provides direct genetic evidence of a key role for Pax-3 in normal neural development.

Genetic linkage studies of the spontaneously arising splotch allele, Sp, were conducted to identify closely linked molecular markers as a preliminary step for the isolation of the mutant gene. Restriction fragment length polymorphism and microsatellite size variation analyses were employed to follow the segregation of Sp in relation to eight or ten loci previously assigned to the proximal portion of mouse chromosome 1. Although results from an interspecific ((Sp/+ x Mus spretus)F1-Sp x C57BL/6J) backcross study were inconclusive, a panel of 125 intraspecific ((Sp/+ x CBA/J)F1-Sp x CBA/J) backcross mice positioned the Sp gene 0.8 $ pm$ 0.8 centiMorgans distal to the Vil/Des/Inha loci and detected no recombinant between the mutant allele and the murine paired box gene, Pax-3, positioning this locus within 2.9 centiMorgans of Sp (95% confidence limits). Concurrent research has identified alterations in Pax-3 in several Sp allelic variants; thus, this study provides additional genetic evidence in support of the candidacy of Pax-3 for the Sp locus. Effects of genetic background on the penetrance and expression of Sp were also observed.