We are in the midst of a revolution in our ability to understand the molecular basis of the skeletal dysplasias. Innovations in genome sequence analysis have provided the opportunity to identify the mutations associated with the 100+ clinically distinct skeletal dysplasias for which an associated gene has yet to be found. The clinical resources of the International Skeletal Dysplasia Registry, the largest worldwide registry of cases from skeletal dysplasia patients, are ideally suited for such studies, having both the depth and breadth of disorders that can be solved using a genomic approach. Each of the disorders to be studied will provide new insights into the complex biology of the skeleton, and will do so in a clinical context. Importantly, genomic approaches will allow us to define the genetic basis of disorders in which traditional genetic approaches are impossible, such as phenotypes produced by new dominant mutations.
In Specific Aim 1, we will study dominant disorders including acrodysostosis, SMD corner fracture type and forms of multiple epiphyseal dysplasia in which the known genes have been excluded.
In Specific Aim 2, recessively inherited phenotypes will be studied including asphyxiating thoracic dystrophy (ATD or Jeune syndrome), opsismodysplasia, a perinatal lethal phenotype with the spondylodysplastic group of disorders, and recessive forms of pseudoachondroplasia and spondyloepiphyseal dysplasia. The genes associated with all of these phenotypes will be defined by exome sequencing. Functional validation will identify the biochemical mechanisms associated with these disorders and begin to explore pathogenesis. The results will reveal new molecular mechanisms for the skeletal dysplasias and define the normal functions of the genes we identify.

Public Health Relevance

The results of these studies will provide immediate translational benefit by providing accurate genetic counseling to families with these conditions as well as opportunities for genetic testing. The results will reveal new molecules and pathways essential for normal skeletal development as well as opportunities for mechanistic studies leading to rational strategies for therapies aimed at ameliorating these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR062651-01A1
Application #
8503380
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Tyree, Bernadette
Project Start
2013-03-01
Project End
2018-04-30
Budget Start
2013-03-01
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$348,717
Indirect Cost
$118,031
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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Murali, Chaya; Lu, James T; Jain, Mahim et al. (2014) Diagnosis of ALG12-CDG by exome sequencing in a case of severe skeletal dysplasia. Mol Genet Metab Rep 1:213-219
Leddy, Holly A; McNulty, Amy L; Lee, Suk Hee et al. (2014) Follistatin in chondrocytes: the link between TRPV4 channelopathies and skeletal malformations. FASEB J 28:2525-37
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
Laine, Christine M; Joeng, Kyu Sang; Campeau, Philippe M et al. (2013) WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta. N Engl J Med 368:1809-16