Abstract

Genetic studies of structural anomalies in humans help to better understand the underlying basis for normal and abnormal embryological development. We have studied the most common brain anomaly in humans, holoprosencephaly (HPE), a structural defect of the developing forebrain and midface. HPE is a genetically heterogeneous disorder associated with various chromosomal anomalies. Recently, mutations in the human Sonic Hedgehog (SHH) gene were shown to cause familial forms of HPE. Furthermore, anomalies in the cholesterol biosynthesis were found in a genetic syndrome associated with HPE. Thus, other yet unidentified HPE causing genes are postulated to be part of the SHH signaling pathway or are involved in the cholesterol biosynthesis. Lanosterol synthase (LS), is the key enzyme involved in the first step of the cholesterol synthesis. The LS gene has been mapped to human chromosome 21q22.3, a region known to be deleted in some HPE patients. Mutational analysis of the LS gene in HPE patients is now in progress to determine whether LS is another HPE candidate gene.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Intramural Research (Z01)
Project #
1Z01HG000115-01
Application #
6162622
Study Section
Molecular Genetics B Study Section (MGB)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
National Human Genome Research Institute
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Arcos-Burgos, M; Castellanos, F X; Konecki, D et al. (2004) Pedigree disequilibrium test (PDT) replicates association and linkage between DRD4 and ADHD in multigenerational and extended pedigrees from a genetic isolate. Mol Psychiatry 9:252-9
Schimmenti, Lisa A; de la Cruz, June; Lewis, Richard Alan et al. (2003) Novel mutation in sonic hedgehog in non-syndromic colobomatous microphthalmia. Am J Med Genet A 116A:215-21
Schell-Apacik, Can; Rivero, Mariel; Knepper, Jessica L et al. (2003) SONIC HEDGEHOG mutations causing human holoprosencephaly impair neural patterning activity. Hum Genet 113:170-7
Edison, Robin; Muenke, Maximilian (2003) The interplay of genetic and environmental factors in craniofacial morphogenesis: holoprosencephaly and the role of cholesterol. Congenit Anom (Kyoto) 43:1-21
Roessler, Erich; Muenke, Maximilian (2003) How a Hedgehog might see holoprosencephaly. Hum Mol Genet 12 Spec No 1:R15-25
Heussler, H S; Suri, M; Young, I D et al. (2002) Extreme variability of expression of a Sonic Hedgehog mutation: attention difficulties and holoprosencephaly. Arch Dis Child 86:293-6
Karkera, J D; Izraeli, S; Roessler, E et al. (2002) The genomic structure, chromosomal localization, and analysis of SIL as a candidate gene for holoprosencephaly. Cytogenet Genome Res 97:62-7
Arcos-Burgos, M; Castellanos, F X; Lopera, F et al. (2002) Attention-deficit/hyperactivity disorder (ADHD): feasibility of linkage analysis in a genetic isolate using extended and multigenerational pedigrees. Clin Genet 61:335-43
Redlinger-Grosse, Krista; Bernhardt, Barbara A; Berg, Kate et al. (2002) The decision to continue: the experiences and needs of parents who receive a prenatal diagnosis of holoprosencephaly. Am J Med Genet 112:369-78
de la Cruz, June M; Bamford, Richard N; Burdine, Rebecca D et al. (2002) A loss-of-function mutation in the CFC domain of TDGF1 is associated with human forebrain defects. Hum Genet 110:422-8

Showing the most recent 10 out of 17 publications