The goals of this project are to use novel mathematical and genetic approaches to identify loci and disease genes for recessively inherited chondrodysplasias, disorders affecting the craniofacial, axial and appendicular skeleton, thereby revealing new mechanisms of disease. The project will test the following hypotheses: First, that ancestral identity-by-descent can be used to identify loci for recessive disorders in small, consanguineous families. Second, that identifying genes selectively expressed in cartilage is an efficient way to filter genes in a linked interval and quickly identify the disease gene. Third, that massively parallel sequence analysis of all genes in a linked interval can be used to identify skeletal dysplasia disease genes that are not selectively expressed in cartilage. These hypotheses will be tested under two Specific Aims: I. To identify loci for recessively inherited skeletal dysplasia phenotypes using ancestral identity-by-descent mapping. Using small numbers of consanguineous families, a novel mathematical ancestral identity-by-descent method will be applied to whole genome single nucleotide polymorphism data to identify genomic intervals associated with skeletal dysplasias of unknown etiology, thereby localizing the disease genes for these phenotypes. II. To identify novel skeletal dysplasia disease genes using a combination of cartilage selective gene expression and massively parallel sequence analysis. Genes within the linked intervals identified under Aim I will be prioritized for mutation analysis by cartilage- selective gene expression. For the disease genes not identifiable by tissue-selective gene expression, each exon of every gene in the linked interval will be captured using custom arrays, and massively parallel sequence analysis will be used for mutation analysis. The results are expected to reveal previously unknown mechanisms and pathways essential for normal skeletal development.

Public Health Relevance

The proposed work will define the genetic basis for human disorders of skeletal development, disorders that affect the craniofacial, axial and appendicular skeleton. The study will reveal and provide clinical context for genes that are important in this process. Translational application of the findings will include DNA diagnosis opportunities for families and potential new treatments based on the specific genes and pathways identified.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE019567-05
Application #
8250831
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Scholnick, Steven
Project Start
2009-07-29
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$380,968
Indirect Cost
$133,586
Name
University of California Los Angeles
Department
Orthopedics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Saitta, Biagio; Passarini, Jenna; Sareen, Dhruv et al. (2014) Patient-derived skeletal dysplasia induced pluripotent stem cells display abnormal chondrogenic marker expression and regulation by BMP2 and TGF?1. Stem Cells Dev 23:1464-78
Li, Bing; Krakow, Deborah; Nickerson, Deborah A et al. (2014) Opsismodysplasia resulting from an insertion mutation in the SH2 domain, which destabilizes INPPL1. Am J Med Genet A 164A:2407-11
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Funari, Vincent A; Krakow, Deborah; Nevarez, Lisette et al. (2010) BMPER mutation in diaphanospondylodysostosis identified by ancestral autozygosity mapping and targeted high-throughput sequencing. Am J Hum Genet 87:532-7

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