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.
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.
|Duran, Ivan; Martin, Jorge H; Weis, Mary Ann et al. (2017) A Chaperone Complex Formed by HSP47, FKBP65, and BiP Modulates Telopeptide Lysyl Hydroxylation of Type I Procollagen. J Bone Miner Res 32:1309-1319|
|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|
|Balasubramanian, Karthika; Li, Bing; Krakow, Deborah et al. (2017) MED resulting from recessively inherited mutations in the gene encoding calcium-activated nucleotidase CANT1. Am J Med Genet A 173:2415-2421|
|Egunsola, Adetutu T; Bae, Yangjin; Jiang, Ming-Ming et al. (2017) Loss of DDRGK1 modulates SOX9 ubiquitination in spondyloepimetaphyseal dysplasia. J Clin Invest 127:1475-1484|
|Zieba, Jennifer; Zhang, Wenjuan; Chong, Jessica X et al. (2017) A postnatal role for embryonic myosin revealed by MYH3 mutations that alter TGF? signaling and cause autosomal dominant spondylocarpotarsal synostosis. Sci Rep 7:41803|
|Li, Bing; Balasubramanian, Karthika; Krakow, Deborah et al. (2017) Genes uniquely expressed in human growth plate chondrocytes uncover a distinct regulatory network. BMC Genomics 18:983|
|Toriyama, Michinori; Lee, Chanjae; Taylor, S Paige et al. (2016) The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery. Nat Genet 48:648-56|
|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|
|Weinstein, Michael M; Kang, Taekyu; Lachman, Ralph S et al. (2016) Somatic mosaicism for a lethal TRPV4 mutation results in non-lethal metatropic dysplasia. Am J Med Genet A 170:3298-3302|
|Krakow, Deborah; Cohn, Daniel H; Wilcox, William R et al. (2016) Clinical and radiographic delineation of Bent Bone Dysplasia-FGFR2 type or Bent Bone Dysplasia with Distinctive Clavicles and Angel-shaped Phalanges. Am J Med Genet A 170:2652-61|
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