Department of Veterinary Clinical Sciences, North Carolina State University, Raleigh, NC, 27607, USA.
Department of Veterinary Clinical Sciences, University of Minnesota, Saint Paul, MN, 55108, USA.
Orphanet J Rare Dis. 2021 Feb 27;16(1):108. doi: 10.1186/s13023-021-01740-5.
Familial hypertrophic cardiomyopathy is a common inherited cardiovascular disorder in people. Many causal mutations have been identified, but about 40% of cases do not have a known causative mutation. Mutations in the ALMS1 gene are associated with the development of Alstrom syndrome, a multisystem familial disease that can include cardiomyopathy (dilated, restrictive). Hypertrophic cardiomyopathy has not been described. The ALMS1 gene is a large gene that encodes for a ubiquitously expressed protein. The function of the protein is not well understood although it is believed to be associated with energy metabolism and homeostasis, cell differentiation and cell cycle control. The ALMS1 protein has also been shown to be involved in the regulation of cell cycle proliferation in perinatal cardiomyocytes. Although cardiomyocyte cell division and replication in mammals generally declines soon after birth, inhibition of ALMS1 expression in mice lead to increased cardiomyocyte proliferation, and deficiency of Alstrom protein has been suggested to impair post-natal cardiomyocyte cell cycle arrest. Here we describe the association of familial hypertrophic cardiomyopathy in Sphynx cats with a novel ALMS1 mutation.
A G/C variant was identified in exon 12 (human exon 13) of the ALMS1 gene in affected cats and was positively associated with the presence of hypertrophic cardiomyopathy in the feline population (p < 0.0001). The variant was predicted to change a highly conserved nonpolar Glycine to a positively charged Arginine. This was predicted to be a deleterious change by three in silico programs. Protein prediction programs indicated that the variant changed the protein structure in this region from a coil to a helix. Light microscopy findings included myofiber disarray with interstitial fibrosis with significantly more nuclear proliferative activity in the affected cats than controls (p < 0.0001).
This study demonstrates a novel form of cardiomyopathy associated with ALMS1 in the cat. Familial hypertrophic cardiomyopathy is a disease of genetic heterogeneity; many of the known causative genes encoding for sarcomeric proteins. Our findings suggest that variants in genes involved with cardiac development and cell regulation, like the ALMS1 gene, may deserve further consideration for association with familial hypertrophic cardiomyopathy.
家族性肥厚型心肌病是一种常见的遗传性心血管疾病。已经发现了许多致病突变，但约有 40%的病例没有已知的致病突变。ALMS1 基因突变与 Alstrom 综合征的发生有关，Alstrom 综合征是一种多系统家族性疾病，可包括心肌病（扩张型、限制型）。尚未描述肥厚型心肌病。ALMS1 基因是一个编码广泛表达蛋白的大基因。尽管人们认为该蛋白与能量代谢和内稳态、细胞分化和细胞周期控制有关，但该蛋白的功能尚不清楚。ALMS1 蛋白还被证明参与调节围生期心肌细胞的细胞周期增殖。尽管哺乳动物的心肌细胞分裂和复制通常在出生后不久就会下降，但在小鼠中抑制 ALMS1 表达会导致心肌细胞增殖增加，并且已经提出 Alstrom 蛋白缺乏会损害出生后心肌细胞的细胞周期阻滞。在这里，我们描述了与斯芬克斯猫家族性肥厚型心肌病相关的新型 ALMS1 突变。
在受影响的猫中，在 ALMS1 基因的外显子 12（人类外显子 13）中发现了一个 G/C 变体，并且与猫群中肥厚型心肌病的存在呈正相关（p<0.0001）。该变体预计会将高度保守的非极性甘氨酸改变为带正电荷的精氨酸。这三个计算机程序预测这是一种有害的变化。蛋白质预测程序表明，该变体使该区域的蛋白质结构从线圈变为螺旋。光镜检查结果包括肌纤维排列紊乱伴间质纤维化，受影响的猫比对照组有更多的核增殖活性（p<0.0001）。
本研究在猫中证明了一种与 ALMS1 相关的新型心肌病。家族性肥厚型心肌病是一种遗传异质性疾病；许多已知的致病基因编码肌节蛋白。我们的发现表明，与心脏发育和细胞调节相关的基因（如 ALMS1 基因）中的变体可能值得进一步考虑与家族性肥厚型心肌病相关。
