GALACTOCEREBROSIDASE DEFICIENCY IN THE DOG - MODEL OF KRABBE DISEASE IN HUMANS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。球状细胞白质营养不良（GLD）或克拉伯病是一种常染色体隐性遗传的神经系统疾病，由溶酶体酶半乳糖脑苷酶（GALC）基因编码突变引起。GALC负责特定半乳糖脂质的降解，包括一些在致密、稳定的髓磷脂生产中很重要的半乳糖脂质的降解。未能充分降解半乳糖神经酰胺和半乳糖神经氨酸（半乳糖神经氨酸）导致在GLD感染的人和动物组织中观察到的特征性病理结果。这些半乳糖鞘脂通常在活跃的髓鞘形成过程中合成，而精神肽在GALC活性非常低的个体中积累。精神素对形成髓磷脂的少突胶质细胞有剧毒，导致它们死亡，并在尸检时发现髓磷脂缺乏。虽然大多数人类患者在6个月前出现症状并在18个月前死亡，但年龄较大的儿童和成人也可被诊断为GLD。目前唯一可用的治疗方法是异源骨髓移植（BMT）。这种疾病有三种自然发生的动物模型，抽搐鼠，凯恩和西部高地白梗，和恒河猴。人类、老鼠和猴子的GALC基因已经在杰斐逊大学医学院大卫·温格博士的实验室里被克隆和鉴定。1996年报道了克隆凯恩和西高地白梗的基因。该繁殖载体犬群由转诊中心与育种人员合作建立，编号为RR02512。然而，该菌落随后被转移到温格博士的资助下，并通过温格博士长期以来对这种疾病的NIH资助的分包合同，在兽医学院的动物护理设施中得到维护。一些支持育种，诊断测试和儿科护理是由转诊中心人员提供的。

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. Globoid cell leukodystrophy (GLD) or Krabbe disease is an autosomal recessively inherited neurological disease caused by mutations in the gene coding for the lysosomal enzyme galacto-cerebrosidase (GALC). GALC is responsible for the degradation of specific galactolipids, including several that are important in the production of compact, stable myelin. A failure to adequately degrade galactosylceramide and psychosine (galactosylsphingosine) results in the characteristic pathological findings observed in tissue from humans and animals affected with GLD. These galactosphingolipids are normally synthesized during active myelination, and psychosine accumulates in individuals with very low GALC activity. Psychosine is highly toxic to the myelin-forming oligodendrocytes, causing their death and the paucity of myelin found on autopsy. While most human patients present with symptoms before six months of age and die before 18 months of age, older children and adults can also be diagnosed with GLD. The only treatment available at this time is heterologous bone marrow transplantation (BMT). This disease has three naturally occurring animal models, the twitcher mouse, the Cairn and West Highland White terriers, and the rhesus monkey. The human, mouse, and monkey GALC genes have been cloned and characterized in the laboratory of David Wenger, PhD, at the Jefferson University School of Medicine. Cloning of the gene in Cairn and West Highland White Terriers was reported in 1996. The colony of breeding carrier dogs was established by the Referral Center by working with breeders and was maintained RR02512. However, the colony was subsequently transferred to Dr. Wenger¿s grant and have been maintained within the Veterinary School¿s animal care facilities by a subcontract from Dr. Wenger¿s long-standing NIH grant on this disorder. Some support for breeding, diagnostic testing, and pediatric care is provided by the Referral Center personnel.