Recurrence risks for neural tube defects in siblings of patients with lipomyelomeningocele.

PURPOSE: Neural tube defects (NTDs) are a group of widely varying congenital malformations resulting from incomplete or improper fusion of the neural tube during embryonic development. NTDs are traditionally classified by the presence or absence of a layer of skin covering the spinal defect. Although a genetic component has been well established in the etiology of open NTDs, studies examining the genetics of closed NTDs such as lipomyelomeningocele are rare. We and others have previously observed families in which multiple members were affected with a broad spectrum of NTDs, suggesting the possibility of a common genetic etiology. METHODS: We calculated the sibling recurrence risk in 52 pedigrees in which the proband was diagnosed with lipomyelomeningocele (LMM), defining recurrence broadly to include both closed and open neural tube defects. RESULTS: Although no recurrences of LMM were observed among younger siblings, one younger sibling had myelomeningocele, yielding an estimate of recurrence risk of 0.04 (95% CI 0.01-0.20). When all siblings of the proband were included, two additional affected siblings were identified, one with anencephaly and another with fatty filum, yielding an estimate of recurrence risk of 0.043 (95% CI 0.01-0.12). CONCLUSIONS: Although the sample size is small, these data are not inconsistent with recurrence risks for myelomeningocele, ranging from 2% to 5% in siblings. These data suggest the underlying genetic basis for closed defects may be the same or closely related to that for myelomeningocele in some families, although a larger sample will be necessary before these data are appropriate for use in a clinical setting. Further characterizations, including whether risk for recurrence of NTDs or LMM in families in which the proband is affected with LMM are altered by folate supplementation, may shed light on the underlying genetics.

Positive and negative regulation of the gamma-secretase activity by nicastrin in a murine model.

Nicastrin is a component of the gamma-secretase complex that has been shown to adhere to presenilin-1 (PS1), Notch, and APP. Here we demonstrate that Nicastrin-deficient mice showed a phenotype that is indistinguishable from PS1/PS2 double knock-out mice, whereas heterozygotes were healthy and viable. Fibroblasts derived from Nicastrin-deficient embryos were unable to generate amyloid beta-peptide and failed to release the intracellular domain of APP- or Notch1-Gal4-VP16 fusion proteins. Additionally, C- and N-terminal fragments of PS1 and the C-terminal fragments of PS2 were not detectable in Nicastrin-null fibroblasts, whereas full-length PS1 accumulated in null fibroblasts, indicating that Nicastrin is required for the endoproteolytic processing of presenilins. Interestingly, cells derived from Nicastrin heterozygotes produced relatively higher levels of amyloid beta-peptide whether the source was endogenous mouse or transfected human APP. These data demonstrate that Nicastrin is essential for the gamma-secretase cleavage of APP and Notch in mammalian cells and that Nicastrin has both positive and negative functions in the regulation of gamma-secretase activity.

Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells.

Neural stem cells, which exhibit self-renewal and multipotentiality, are generated in early embryonic brains and maintained throughout the lifespan. The mechanisms of their generation and maintenance are largely unknown. Here, we show that neural stem cells are generated independent of RBP-Jkappa, a key molecule in Notch signaling, by using RBP-Jkappa(-/-) embryonic stem cells in an embryonic stem cell-derived neurosphere assay. However, Notch pathway molecules are essential for the maintenance of neural stem cells; they are depleted in the early embryonic brains of RBP-Jkappa(-/-) or Notch1(-/-) mice. Neural stem cells also are depleted in embryonic brains deficient for the presenilin1 (PS1) gene, a key regulator in Notch signaling, and are reduced in PS1(+/-) adult brains. Both neuronal and glial differentiation in vitro were enhanced by attenuation of Notch signaling and suppressed by expressing an active form of Notch1. These data are consistent with a role for Notch signaling in the maintenance of the neural stem cell, and inconsistent with a role in a neuronal/glial fate switch.

Possible association of NTDs with a polyhistidine tract polymorphism in the ZIC2 gene.

Neural tube defects (NTDs) and brain malformations represent a common finding in chromosome 13q deletion patients. Hemizygosity for ZIC2, which is located in the 13q32 critical deletion region, results in holoprosencephaly (HPE) in humans, and diminished expression of ZIC2 results in HPE as well as lumbosacral NTDs in mice. Taken together, these observations led us to hypothesize that ZIC2 mutations may be a cause of isolated NTD. To test this, we screened 192 NTD patients for mutations in ZIC2. While we did not find ZIC2 mutations in these patients, we did find some evidence of a possible association between a histidine tract polymorphism in ZIC2 and NTDs. Our sample was too small to reach definitive conclusions, but the evidence is sufficiently intriguing to encourage further research. If this association is confirmed, subtle alterations in ZIC2 activity may confer a risk of NTD.