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Identification and characterization of hydin, a large novel gene disrupted in a murine model of congenital hydrocephalus

Davy, Brian Edwin
http://rave.ohiolink.edu/etdc/view?acc_num=osu1086103379

Abstract Details

2004, Doctor of Philosophy, Ohio State University, Molecular, Cellular, and Developmental Biology.
Congenital hydrocephalus is a frequent human birth defect, occurring with an estimated incidence of 1 in 1000 live births. While a significant portion of human hydrocephalus is genetic in origin, the molecular genetics of this disease remains poorly understood. The murine autosomal-recessive mutation hydrocephalus-3 (hy3) results in lethal communicating hydrocephalus with perinatal onset. A recently described transgenic insertional mutation, OVE459, represents a new allele of hy3. In previous work, the OVE459 transgene insertion site was cloned, and a wild-type BAC clone encompassing the transgene insertion site was subsequently identified. Here, we describe the isolation of expressed sequences on this BAC clone by direct cDNA selection. Selected cDNAs facilitated the identification of two novel candidate genes, Hydin and Vac14. Hydin consists of at least 86 exons spanning more than 340 kb on mouse chromosome 8. The full-length Hydin transcript is nearly 16 kb and encodes a putative 5099 amino acid protein. Hydin is expressed in compartments of the brain that are directly involved in CSF production and homeostasis. In situ hybridization revealed Hydin transcripts in the choroid plexus and ciliated ependymal cells lining the ventricles at various stages of development and in the adult animal. Outside the central nervous system, Hydin is specifically expressed in cell-types that possess 9+2 cilia or flagella. The OVE459 transgene insertion resulted in a rearrangement within Hydin, disrupting the order of Hydin exons in these mice. Northern analysis revealed a marked reduction of Hydin mRNA levels in OVE459 and hy3 homozygotes relative to wild-type littermates. Sequencing of all 87 Hydin exons from homozygous hy3 genomic DNA revealed a single CG base-pair deletion in exon 15, causing a premature termination signal two codons downstream of the deletion. From this evidence, we conclude that Hydin is the disrupted gene in the OVE459/hy3 mouse model of congenital hydrocephalus. The Hydin gene product does not resemble any previously identified protein with the exception of a 314 amino acid region with homology to caldesmon, an actin-binding protein. To facilitate future investigations concerning Hydin function, a conditional targeting construct generated via recombineering was used to target Hydin exon 15 in ES cells.
Michael Robinson (Advisor)
157 p.
Biology, Genetics
hydrocephalus; hy3; Hydin; mouse models

Recommended Citations

Citations

  • Davy, B. E. (2004). Identification and characterization of hydin, a large novel gene disrupted in a murine model of congenital hydrocephalus [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1086103379

    APA Style (7th edition)

  • Davy, Brian. Identification and characterization of hydin, a large novel gene disrupted in a murine model of congenital hydrocephalus. 2004. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1086103379.

    MLA Style (8th edition)

  • Davy, Brian. "Identification and characterization of hydin, a large novel gene disrupted in a murine model of congenital hydrocephalus." Doctoral dissertation, Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=osu1086103379

    Chicago Manual of Style (17th edition)

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This open access ETD is published by The Ohio State University and OhioLINK.