Investigation of Quantitative Trait Loci in Cavalier King Charles Spaniels with and without Chiari-like Malformation and Syringomyelia

项目概要/摘要： Chiari I型畸形（CM1）是一种发育障碍，估计影响215，000名美国人。是 其特征在于枕骨大孔下方的小脑扁桃体的尾部疝出，并且经常 与脊髓灰质炎（SM）有关。在骑士查理王猎犬（CKCS），像人一样， 畸形导致大脑和颅骨不匹配，产生相对较小的尾窝， 颅静脉窦和颅骨孔狭窄。这些变化 共同产生脑脊液（CSF）的湍流和脊髓内SM的发展。 CKCS中的CMSM复合物引起主要局限于头颈部的严重神经病理性疼痛 表现为幻肢搔抓（搔抓头部和颈部，但不接触皮肤），对 触摸，并在痛苦中尖叫。类似地，CM1在人类中的临床表现由以下表现主导： 神经性疼痛，包括枕部和上颈部疼痛，以及上颈部的烧灼感 四肢人类和犬类疾病的遗传基础已经被推断出来，然而， 仍然未知。我们认为CKCS中的CMSM是人类CM1的模型， 这个品种将与人类的生存状况息息相关在这个项目中，我们将利用基因 狗品种的同质性，以确定与CMSM相关的新的遗传变异。这些变体，以及 他们强调的途径，然后可以在CM1患者中进行研究。 我们的实验室已经开发了临床计量工具来量化临床表型，并具有广泛的 在MRI上量化CKCS中CMSM的形态学特征的经验。与博士合作。 Trudy Mackay的遗传学实验室，我们将进行关联映射，以确定使用两种情况下的变体- 控制和数量性状研究设计。本研究的主要目的是确定与 但将对这些基因座进行初步检查，以确定是否存在致病突变。我们 建议使用基于形态MRI的CMSM严重程度的分类和连续测量 结果，以及神经性疼痛体征的测量，包括主人报告的问卷数据，以及 神经学检查结果。我们假设与CMSM相关的数量性状位点（QTL） 在CKCS中，可以使用全基因组关联研究和定量表型来鉴定。在 完成这项研究后，我们将发现与CMSM形态学变化相关的新基因座 和/或神经性疼痛，其将被研究与所述性状相关的遗传变体。这项工作将 为CM1和相关神经性疼痛的遗传基础的合作研究铺平道路， 人类

Project Summary/Abstract: Chiari-type I malformation (CM1) is a developmental disorder estimated to affect 215,000 Americans. It is characterized by caudal herniation of the cerebellar tonsils below the foramen magnum and is frequently associated with syringomyelia (SM). In Cavalier King Charles Spaniels (CKCS), like people, Chiari-like malformations result in a brain and skull mismatch that produces a relatively small caudal fossa with crowding of the foramen magnum, and stenosis of the cranial venous sinuses and skull foramina. These changes conspire to produce turbulent flow of cerebrospinal fluid (CSF) and development of SM within the spinal cord. The CMSM complex in CKCS causes severe neuropathic pain mainly localized to the head and neck region manifesting as phantom scratching (scratching of the head and neck without making skin contact), sensitivity to touch, and screaming in pain. Similarly, clinical presentation of CM1 in humans is dominated by manifestations of neuropathic pain including occipital and upper cervical pain, and burning sensations of the upper extremities. A genetic basis for the human and canine condition have been inferred, however, many causes remain unknown. We propose that CMSM in CKCS is a model of CM1 in humans and that genetic discovery in this breed will have relevance for the human condition. In this project, we will leverage the genetic homogeneity of dog breeds to identify novel genetic variants associated with CMSM. These variants, and the pathways that they highlight, can then be investigated in humans with CM1. Our laboratory has developed clinical metrology tools to quantify the clinical phenotype and has extensive experience quantifying the morphological characteristics of CMSM in CKCS on MRI. In collaboration with Dr. Trudy Mackay's genetics laboratory, we will perform association mapping to identify variants using both case- control and quantitative trait study design. The primary purpose of this study is to identify loci associated with CMSM in CKCS but a preliminary examination of these loci for causative mutations will be performed. We propose to use both categorical and continuous measures of severity of CMSM based on morphologic MRI findings, as well as measures of neuropathic pain signs including owner-reported questionnaire data, and neurological examination findings. We hypothesize that quantitative trait loci (QTL) associated with CMSM in CKCS can be identified using a genome-wide association study and quantitative phenotypes. At the completion of this study, we will have uncovered novel loci associated with CMSM morphological changes and/or neuropathic pain that will be investigated for genetic variants associated with the traits. This work will pave the road for collaborative studies on the genetic basis of CM1 and associated neuropathic pain in humans.