CEREBELLAR HYPOPLASIA, FETAL AKINESIS, AND ARTHROGRYPOSIS IN DOGS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。在上述患有先天性甲状腺功能减退症的同一群狗中，约翰·法伊夫博士发现了一种神经发育障碍，这种疾病被分离为完全穿透性常染色体隐性遗传特征，在子宫内或出生时致命。受影响的幼崽在怀孕的最后一周失去运动能力，并在尝试呼吸几次后死产或出生时死亡。受影响的幼鼠有四边形关节畸形、脊柱侧弯和严重的小脑发育不良。组织学检查显示小脑浦肯野和颗粒层细胞丢失，中枢神经系统多个核团变性神经元，神经源性脊肌萎缩。在许多方面，这种疾病类似于桥小脑发育不全伴前角细胞受累(PCHI型；OMIM#607596)，尚未确定致病基因或连锁基因。虽然与促甲状腺激素缺乏的狗属于同一家族，但这两种缺陷是独立分离的。发生这种疾病的狗群最近被转移到密歇根州立大学。去年，Henthorn博士和Fyfe博士向NINDS提交的一项合作提案获得了资金，以揭示中枢神经系统发育障碍的分子基础。一只没有血缘关系的狗被培育成一只被证实为缺陷携带者的狗，其后代被安置在宾夕法尼亚大学。确定携带者状态的繁殖已经证明一只雌性作为携带者，其他试验繁殖正在进行中。选择这种育种是为了通过增加整个基因组中标记的杂合性来加强未来的连锁研究。我们已经启动了与这种疾病相关的基因组扫描，同时在同一家族的狗中寻找与甲状腺功能减退有关的标记。已发现与CFA4的初步联系。

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.