Abstract

A study of the complex genetics of brain development has been undertaken with an emphasis on those genes that cause the most common structural forebrain anomaly in humans, holoprosencephaly (HPE). This malformation of the brain can result from either environmental or genetic causes. It is the aim of these investigations to determine the genes responsible for both normal and abnormal brain development through the study of patients with this disorder. Mutations in six such genes has been shown by us to be responsible for approximately one quarter of familial and sporadic cases of HPE (Roessler et al. 1996,1997; Brown et al., 1998; Wallis et al., 1999; Gripp et al., 2000; Ming et al., 2002; dela Cruz et al., 2002). Other genes either related to the hedgehog pathway or located at defined genetic loci may also contribute to HPE and are the subject of active investigation. We anticipate that many genes important for normal brain development will be identified in the search for genetic causes of HPE. In addition, the aim of these investigations is to identify environmental factors that contribute to HPE. Animal models have shown that low maternal cholesterol causes brain anomalies in some offspring. The findings are now being tested in epidemiological studies where low maternal serum cholesterol during pregnancy is correlated with birth outcome.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Intramural Research (Z01)
Project #
1Z01HG000209-06
Application #
7594320
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2007
Total Cost
$1,218,400
Indirect Cost

  Institution

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

  Publications

Agochukwu, Nneamaka Barbara; Solomon, Benjamin D; Doherty, Emily S et al. (2012) Palatal and oral manifestations of Muenke syndrome (FGFR3-related craniosynostosis). J Craniofac Surg 23:664-8
El-Jaick, Kenia B; Powers, Shannon E; Bartholin, Laurent et al. (2007) Functional analysis of mutations in TGIF associated with holoprosencephaly. Mol Genet Metab 90:97-111
Bendavid, C; Haddad, B R; Griffin, A et al. (2006) Multicolour FISH and quantitative PCR can detect submicroscopic deletions in holoprosencephaly patients with a normal karyotype. J Med Genet 43:496-500
Jeong, Yongsu; El-Jaick, Kenia; Roessler, Erich et al. (2006) A functional screen for sonic hedgehog regulatory elements across a 1 Mb interval identifies long-range ventral forebrain enhancers. Development 133:761-72
Edison, Robin J; Muenke, Maximilian (2005) Gestational exposure to lovastatin followed by cardiac malformation misclassified as holoprosencephaly. N Engl J Med 352:2759
Roessler, Erich; Ermilov, Alexandre N; Grange, Dorothy Katherine et al. (2005) A previously unidentified amino-terminal domain regulates transcriptional activity of wild-type and disease-associated human GLI2. Hum Mol Genet 14:2181-8
Edison, Robin J; Muenke, Maximilian (2004) Central nervous system and limb anomalies in case reports of first-trimester statin exposure. N Engl J Med 350:1579-82
Edison, Robin J; Muenke, Maximilian (2004) Mechanistic and epidemiologic considerations in the evaluation of adverse birth outcomes following gestational exposure to statins. Am J Med Genet A 131:287-98
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
Roessler, Erich; Du, Yang-Zhu; Mullor, Jose L et al. (2003) Loss-of-function mutations in the human GLI2 gene are associated with pituitary anomalies and holoprosencephaly-like features. Proc Natl Acad Sci U S A 100:13424-9

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