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Genetic studies of multifactorial neural tube closure defects in mice Wu, Mona Kay

Abstract

Anencephaly and spina bifida aperta, defects in neural tube closure, are among the most common serious human birth defects. Neural tube defects (NTD) that occur in the absence of other abnormalities ("nonsyndromic") are generally regarded to be multifactorial threshold traits. Mouse models for nonsyndromic multifactorial anencephaly and spina bifida aperta include the SELH/Bc and "CT" strains. SELH/Bc has 10-30% risk of exencephaly, the equivalent of human anencephaly; the "CT strain" has -3% risk of exencephaly, 10% of spina bifida aperta, and 50% of flexed tail. For each of these models, chromosomal regions containing "risk" genes have been identified. To investigate possible interactions or interchangeability between the genetic risk factors for NTD in the SELH/Bc and "CT strain" we have crossed SELH/Bc with "CT strain" mice and generated a segregating F₂ generation. Scoring for exencephaly, spina bifida, and flexed tails in E14 embryos, results show 0% NTD (0/115) in the F₂ and 4.6% NTD (35/758) in the F₂ generation: 24 exencephaly, 4 spina bifida (2 with flexed tails), and 7 flexed tails (1 with exencephaly). Genotypes for SSLPs marking each "risk region" suggest an association of SELH/Bc risk loci on Chr 13 and 11 with exencephaly and a trend toward an association of a "CT strain" risk locus on Chr 4 with spina bifida and flexed tail. Although SELH/Bc and the "CT strain" are both multifactorial systems of NTD, they do not interact to increase the overall risk for NTD in an F₂ . The "CT strain" risk factor at Chr 4 may add to the risk of SELH/Bc or be interchangeable with one of the SELH/Bc factors at Chr 11 or 13 for risk of exencephaly in an F₂ . However, a hypothesis of independent SELH/Bc and "CT strain" causes for exencephaly in the F₂ is not rejected. There was no evidence of interaction between the "CT strain" factors and SELH/Bc factors for spina bifida risk. There may some contribution from the SELH/Bc risk region at Chr 11 to the risk of flexed tail. Inositol supplementation has previously been shown to reduce the frequency of spina bifida aperta in the "CT strain". Therefore, in order to investigate a possible similarity of environmental component of risk of NTD between SELH/Bc and "CT strain", the effect of maternal administration of myo-inositol in drinking water on frequency of exencephaly in the SELH/Bc strain was assessed. There was no evidence for a protective effect of myo- inositol supplementation. Concurrently, a small backcross study was done between the "CT strain" and normal BXA-7/Pgn strain, backcrossed to the "CT strain", to find out the frequency of spina bifida and exencephaly in BCi embryos. 19% of BC₁ individuals were affected (1.0% exencephaly with flexed tail, 1.0% spina bifida aperta with flexed tail, and 17%

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