The purpose of this training grant is to help establish the applicant's independent research career in the field of clinical neurogenetics by investigating the molecular and genetic basis of Joubert syndrome (JS), an autosomal recessive malformation syndrome associated with agenesis of the cerebellar vermis and brainstem malformations. The training environment is the laboratory of Dr. Phillip Chance at the University of Washington, with a track record in mapping and identifying the genes for hereditary neurological disorders. Clinical core features of JS are hypotonia, developmental delay, abnormal respiratory patterns and unusual eye movements. Furthermore, JS exhibits variable additional clinical features (e.g., retinopathy, nephropathy), and is likely to represent a spectrum of disorders with the common feature of cerebellar vermis hypoplasia. Genetic locus heterogeneity is evident. Although loci for JS have been proposed on chromosomes 9q34 and 17pl 1.2, in the majority of JS pedigrees, the locus is unknown and no specific gene has yet been found to be causal for JS. Genes crucial to cerebellar and brainstem development are functional JS candidates, particularly genes specifying the vermian domain and granule cell lineage during cerebellar development. To map an additional gene (or genes) for JS and to determine the molecular basis of this and related disorders, I propose to: 1) Ascertain and collect medical records and blood samples for DNA isolation form multiple families with JS, particularly consanguineous and multiplex pedigrees, 2) develop a prioritized list of candidate genes for JS utilizing genetic methods that include focused haplotype analysis of these genes in consanguineous and multiplex families as well as functional examination of candidate gene expression in human fetal brain tissue, and 3) screen the best candidate genes for mutations in individuals with JS. The fourth and final goal will be to carry out a genome-wide linkage scan to identify loci for JS utilizing a combination of methods employing homozygosity mapping and/or high-resolution linkage analysis in multiplex pedigrees. This project will allow the applicant to complement her experience in clinical genetics and developmental molecular biology with the clinical research skills to define the molecular basis of this important group of cerebellar malformation syndromes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23NS045832-05
Application #
7201653
Study Section
NST-2 Subcommittee (NST)
Program Officer
Riddle, Robert D
Project Start
2003-04-16
Project End
2008-08-28
Budget Start
2007-03-01
Budget End
2008-08-28
Support Year
5
Fiscal Year
2007
Total Cost
$166,271
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Slaats, Gisela G; Isabella, Christine R; Kroes, Hester Y et al. (2016) MKS1 regulates ciliary INPP5E levels in Joubert syndrome. J Med Genet 53:62-72
Bachmann-Gagescu, R; Dempsey, J C; Phelps, I G et al. (2015) Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity. J Med Genet 52:514-22
Doherty, D; Parisi, M A; Finn, L S et al. (2010) Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis). J Med Genet 47:8-21
Parisi, Melissa A (2009) Clinical and molecular features of Joubert syndrome and related disorders. Am J Med Genet C Semin Med Genet 151C:326-40
Gorden, Nicholas T; Arts, Heleen H; Parisi, Melissa A et al. (2008) CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290. Am J Hum Genet 83:559-71
Arts, Heleen H; Doherty, Dan; van Beersum, Sylvia E C et al. (2007) Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome. Nat Genet 39:882-8
Parisi, Melissa A; Doherty, Dan; Chance, Phillip F et al. (2007) Joubert syndrome (and related disorders) (OMIM 213300). Eur J Hum Genet 15:511-21
Parisi, M A; Doherty, D; Eckert, M L et al. (2006) AHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndrome. J Med Genet 43:334-9
Parisi, Melissa A; Bennett, Craig L; Eckert, Melissa L et al. (2004) The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome. Am J Hum Genet 75:82-91