Schisler Jonathan C, Patterson Cam, Willis Monte S
McAllister Heart Institute, University of North Carolina, Chapel Hill, NC USA.
Department of Pharmacology, University of North Carolina, Chapel Hill, NC USA.
Afr J Cell Pathol. 2016 Apr;6(4):28-36.
Hereditary ataxias are characterized by a slowly progressive loss of gait, hand, speech, and eye coordination and cerebellar atrophy. A subset of these, including hypogonadism, are inherited as autosomal recessive traits involving coding mutations of genes involved in ubiquitination including , and . Cerebellar CHIPopathy (MIM 615768) is a form of autosomal recessive spinocerebellar ataxia (SCAR16) and when accompanied with hypogonadism, clinically resembles the Gordon Holmes Syndrome (GHS). A causal missense mutation in the gene that encodes the carboxy terminus of HSP-70 interacting protein (CHIP) protein was reported for the first time in 2014. CHIP-/- mice were found to phenocopy the motor deficiencies and some aspects of the hypogonadism observed in patients with mutations. However, mechanisms responsible for these deficits are not known.
In a survey of skeletal muscle by transmission electron microscopy.
CHIP-/- mice at 6 months of age were found to have morphological changes consistent with increased sarcoplasmic reticulum compartments in quadriceps muscle and gastrocnemius (toxic oligomers and tubular aggregates), but not in soleus.
Since CHIP has been implicated in ER stress in non-muscle cells, these findings illustrate potential parallel roles of CHIP in the muscle sarcoplasmic reticulum, a hypothesis that may be clinically relevant in a variety of common muscular and cardiac diseases.
遗传性共济失调的特征是步态、手部、言语和眼球协调能力逐渐丧失以及小脑萎缩。其中一部分，包括性腺功能减退，是以常染色体隐性性状遗传的，涉及泛素化相关基因的编码突变，包括[具体基因1]、[具体基因2]和[具体基因3]。小脑CHIP病（MIM 615768）是常染色体隐性脊髓小脑共济失调（SCAR16）的一种形式，当伴有性腺功能减退时，临床上类似于戈登·霍姆斯综合征（GHS）。2014年首次报道了编码HSP - 70相互作用蛋白（CHIP）羧基末端的基因中的一个致病错义突变。发现CHIP基因敲除小鼠表现出与携带该突变的患者所观察到的运动缺陷和性腺功能减退的某些方面相似的表型。然而，导致这些缺陷的机制尚不清楚。
通过透射电子显微镜对骨骼肌进行检查。
发现6个月大的CHIP基因敲除小鼠的形态学变化与股四头肌和腓肠肌（毒性寡聚体和管状聚集体）中肌浆网隔室增加一致，但比目鱼肌中没有这种变化。
由于CHIP已被证明在非肌肉细胞的内质网应激中起作用，这些发现说明了CHIP在肌肉肌浆网中可能具有类似的作用，这一假设可能在多种常见的肌肉和心脏疾病中具有临床相关性。
