laboratory of clinical
genomics
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Owen M. Rennert, MD,
Chief The Laboratory of Clinical Genomics (LCG)
addresses the interface between biological and clinical research as related
to the process of development/differentiation. The Section
on Developmental Genomics, led by Owen Rennert, has focused on defining
the genetic processes that regulate gonad and germ cell development. The
section used microarray and SAGE analysis tools to investigate global gene
expression during spermatogenesis and has established a database that is now
a resource for investigations on processes occurring in differentiating germ
cells. The researchers identified a large number of novel genes
differentially expressed at different stages of germ cell development.
Molecular cloning and characterization of some of the novel genes have led to
the identification of a putative novel role of cytochrome c oxidase in germ
cells. Cloning of the full-length cDNA of a novel gene confirms that the gene
encodes a new isoform of the murine N-terminal acetyltransferase 1. The gene
appears to be active in meiotic germ cells whereas Tex13 and Lin-28 are
active in the mitotic type A spermatogonia. The biological activities of the
three genes in spermatogenesis are currently under investigation. The SAGE database
also provides leads for the identification of a network of antisense
transcripts that are abundantly expressed in germ cells. The section plans to
investigate interactions between sense and antisense transcripts and the
roles of antisense transcription in germ cell development. To understand gene expression and regulation
in early gonad development, members of the section used SAGE to map the
transcriptomes of embryonic gonad of male mice. Their work resulted in the
identification of over 4,700 genes expressed in E10.5 to E12.5 gonads but not
in differentiated germ cells. Examination of the transcriptome data revealed
high-level expression of hemoglobin genes in male embryonic gonads. The
biological implication of this observation is currently under investigation.
Concurrently, the section is examining the effects of mutated luteinizing
hormone receptor (hLHR) on downstream gene expression. Activating mutations
of the hLHR cause familial male-limited precocious puberty and might
predispose the patient to develop testicular neoplasia. Researchers generated
an in vitro cell model and an in vivo transgenic mouse model to
study the role of the mutated receptor on testicular tumorigenesis. Additional collaborative studies in the
laboratory examine patients with nephropathic cystinosis and the
susceptibility for thromboses that may predispose such patients to develop
pseudotumor cerebri. To facilitate detection of at-risk individuals for
development of venous thrombosis, a new screening device is currently under
study. It will allow rapid screening of mutations and polymorphisms reported
to be risk factors for the development of venous thrombosis. During
the past year, the Unit on Pediatric
Genetics, led by Steven
Kaler, has investigated two groups of disorders, the X-linked
recessive disorder called Menkes Kinky Hair disease and the platelet
abnormality known as Bernard-Soulier syndrome. In the case of Menkes Kinky
Hair disease, the unit has investigated the downstream gene-expression
consequences of a defect in the copper-ATP transport system in both clinical
autopsy material and a yeast knockout strain. The investigators studied a
child who had the velo-cardio-facial syndrome with thrombophilia due to
haploinsufficiency of chromosome 22q11. Their research led to the delineation
of platelet glycoprotein GPIbalpha-alpha-beta-beta complex deficiency. |