Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
7R01DE019567-03
Application #
8248345
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Scholnick, Steven
Project Start
2009-07-29
Project End
2013-03-31
Budget Start
2011-03-24
Budget End
2011-03-31
Support Year
3
Fiscal Year
2010
Total Cost
$94,697
Indirect Cost

  Institution

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

  Publications

Kunova Bosakova, Michaela; Varecha, Miroslav; Hampl, Marek et al. (2018) Regulation of ciliary function by fibroblast growth factor signaling identifies FGFR3-related disorders achondroplasia and thanatophoric dysplasia as ciliopathies. Hum Mol Genet 27:1093-1105
Zhang, Wenjuan; Taylor, S Paige; Ennis, Hayley A et al. (2018) Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat 39:152-166
Badiner, N; Taylor, S P; Forlenza, K et al. (2017) Mutations in DYNC2H1, the cytoplasmic dynein 2, heavy chain 1 motor protein gene, cause short-rib polydactyly type I, Saldino-Noonan type. Clin Genet 92:158-165
Paige Taylor, S; Kunova Bosakova, Michaela; Varecha, Miroslav et al. (2016) An inactivating mutation in intestinal cell kinase, ICK, impairs hedgehog signalling and causes short rib-polydactyly syndrome. Hum Mol Genet 25:3998-4011
Aldinger, Kimberly A; Mendelsohn, Nancy J; Chung, Brian Hy et al. (2016) Variable brain phenotype primarily affects the brainstem and cerebellum in patients with osteogenesis imperfecta caused by recessive WNT1 mutations. J Med Genet 53:427-30
Duran, Ivan; Taylor, S Paige; Zhang, Wenjuan et al. (2016) Destabilization of the IFT-B cilia core complex due to mutations in IFT81 causes a Spectrum of Short-Rib Polydactyly Syndrome. Sci Rep 6:34232
Lee, Hane; Nevarez, Lisette; Lachman, Ralph S et al. (2015) A second locus for Schneckenbecken dysplasia identified by a mutation in the gene encoding inositol polyphosphate phosphatase-like 1 (INPPL1). Am J Med Genet A 167A:2470-3
Schmidts, Miriam; Hou, Yuqing; Cortés, Claudio R et al. (2015) TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport. Nat Commun 6:7074
Duran, Ivan; Nevarez, Lisette; Sarukhanov, Anna et al. (2015) HSP47 and FKBP65 cooperate in the synthesis of type I procollagen. Hum Mol Genet 24:1918-28
Martin, Brett M; Ivanova, Margarita H; Sarukhanov, Anna et al. (2014) Prenatal and postnatal findings in serpentine fibula polycystic kidney syndrome and a review of the NOTCH2 spectrum disorders. Am J Med Genet A 164A:2490-5

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