Wiedmer Michaela, Oevermann Anna, Borer-Germann Stephanie E, Gorgas Daniela, Shelton G Diane, Drögemüller Michaela, Jagannathan Vidhya, Henke Diana, Leeb Tosso
Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.
Division of Neurological Sciences, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.
G3 (Bethesda). 2015 Nov 23;6(2):255-62. doi: 10.1534/g3.115.022707.
We observed a hereditary phenotype in Alaskan Huskies that was characterized by polyneuropathy with ocular abnormalities and neuronal vacuolation (POANV). The affected dogs developed a progressive severe ataxia, which led to euthanasia between 8 and 16 months of age. The pedigrees were consistent with a monogenic autosomal recessive inheritance. We localized the causative genetic defect to a 4 Mb interval on chromosome 19 by a combined linkage and homozygosity mapping approach. Whole genome sequencing of one affected dog, an obligate carrier, and an unrelated control revealed a 218-bp SINE insertion into exon 7 of the RAB3GAP1 gene. The SINE insertion was perfectly associated with the disease phenotype in a cohort of 43 Alaskan Huskies, and it was absent from 541 control dogs of diverse other breeds. The SINE insertion induced aberrant splicing and led to a transcript with a greatly altered exon 7. RAB3GAP1 loss-of-function variants in humans cause Warburg Micro Syndrome 1 (WARBM1), which is characterized by additional developmental defects compared to canine POANV, whereas Rab3gap1-deficient mice have a much milder phenotype than either humans or dogs. Thus, the RAB3GAP1 mutant Alaskan Huskies provide an interesting intermediate phenotype that may help to better understand the function of RAB3GAP1 in development. Furthermore, the identification of the presumed causative genetic variant will enable genetic testing to avoid the nonintentional breeding of affected dogs.
我们在阿拉斯加哈士奇犬中观察到一种遗传性表型，其特征为伴有眼部异常和神经元空泡化的多神经病（POANV）。患病犬出现进行性严重共济失调，导致在8至16月龄时实施安乐死。家系分析结果符合单基因常染色体隐性遗传模式。我们通过连锁分析和纯合性定位相结合的方法，将致病基因缺陷定位到19号染色体上一个4 Mb的区间内。对一只患病犬、一只必然携带者和一只无关对照犬进行全基因组测序，结果显示RAB3GAP1基因外显子7中插入了一段218 bp的短散在核元件（SINE）。在一组43只阿拉斯加哈士奇犬中，该SINE插入与疾病表型完全相关，而在541只其他不同品种的对照犬中则未发现。该SINE插入导致异常剪接，并产生一个外显子7发生极大改变的转录本。人类中RAB3GAP1功能缺失变体可导致沃伯格微综合征1型（WARBM1），与犬类POANV相比，其特征为伴有其他发育缺陷，而Rab3gap1基因缺陷的小鼠表型比人类或犬类都要轻得多。因此，RAB3GAP1突变的阿拉斯加哈士奇犬提供了一种有趣的中间表型，可能有助于更好地理解RAB3GAP1在发育过程中的功能。此外，确定推测的致病基因变体将能够进行基因检测，以避免无意中繁殖出患病犬。
