CEREBELLAR HYPOPLASIA, FETAL AKINESIS, AND ARTHROGRYPOSIS IN DOGS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the same colony of dogs with congenital hypothyroidism described above, Dr. John Fyfe has identified a neurodevelopmental disorder that segregates as a fully penetrant autosomal recessive trait, lethal in utero or at birth. Affected pups lose motility during the last week of gestation and are stillborn or die at birth after a few attempts at breathing. Affected pups have quadrilateral arthogryposis, spinal scoliosis, and severe cerebellar hypoplasia. Histologic studies show loss of Purkinje and granular layer cells in the cerebellum, degenerative neurons in multiple nuclei of the CNS, and evidence of neurogenic spinal muscular atrophy. In a number of respects, this disorder resembles pontocerebellar hypoplasia with anterior horn cell involvement (PCH type I; OMIM #607596) for which no disease causing genes nor linked loci have yet been defined. Although present in the same family as the TSH-deficient dogs, the two defects segregate independently. The colony of dogs in which this disorder occurs was recently moved to Michigan State University. In the last year a collaborative proposal by Drs. Henthorn and Fyfe to NINDS has been funded to uncover the molecular basis of the CNS developmental disorder. An unrelated dog was bred to a proven carrier of the defect, and the offspring are housed at University of Pennsylvania. Breedings to determine carrier status have proven one female as a carrier and other test breedings are under way. This breeding was chosen to enhance future linkage studies by increasing heterozygousity of markers throughout the genome. We have initiated a genome scan for linkage to this disorder simultaneously with the search for a marker linked to hypothyroidism in the same family of dogs. Tentative linkage to CFA 4 has been found.