Date of Award

2019-01-01

Degree Name

Master of Science

Department

Biological Sciences

Advisor(s)

Anita M. Quintana

Abstract

We present a patient diagnosed with a multiple congenital anomaly syndrome characterized by scoliosis, intellectual disabilities, and craniofacial defects. Trio-based whole exome sequencing identified compound heterozygous variants in the HSPG2 gene: a maternally inherited c.5998-7A>G variant in the promoter region and a paternally inherited c.4916C>T variant in the coding sequence. HSPG2 encodes for perlecan, a large proteoglycan that plays an important role in cartilage formation, cell adhesion, and basement membrane stability. Mutations in HSPG2 have been associated with Schwartz-Jampel syndrome and Dyssegmental Dysplasia Silverman-Handmaker Type, two disorders characterized by skeletal abnormalities (1). These data indicate a function for HSPG2 in cartilage development/maintenance. However, the mechanisms by which HSPG2 regulates cartilage development are not completely understood. To address this, we performed morpholino-mediated knockdown of hspg2 in zebrafish. Knockdown of hspg2 resulted in a 7% truncation in the mandible and a fusion of the mandibular jaw point at 5 days post fertilization (dpf). We surmised that defects in mandible development were a consequence of neural crest cell (NCC) function, as these multipotent progenitors produce the cartilage of the head and neck. Early NCC development was normal in morphant animals as measured by dlx2a and sox10 expression at 1 dpf. However, subsequent analysis at later stages of development (3-4 dpf) revealed a decrease in the number of sox10 and col2a1a positive cells within the mandibular jaw joint region of morphants relative to control injected embryos. Concurrently, morphants showed a decreased expression of nkx3.2, a jaw joint molecular marker at 2 dpf. Collectively, these data suggest a complex role for hspg2 in jaw joint formation and late stage NCC differentiation.

Language

en

Provenance

Received from ProQuest

File Size

68 pages

File Format

application/pdf

Rights Holder

Barbara Samantha Castellanos

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