A frameshift mutation in HTRA1 expands CARASIL syndrome and peripheral small arterial disease to the Chinese population

Abstract

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a rare hereditary cerebral artery disease. The HtrA serine protease 1 (HTRA1) gene has been identified as the causative gene of CARASIL. Here, we report a novel mutation in the HTRA1 gene in a CARASIL pedigree and explore its pathogenesis at the protein level. Subcutaneous tissue biopsy and HTRA1 gene analysis were performed in a CARASIL patient, and HTRA1 and TGF-β1 protein expression in subcutaneous tissue and cultured fibroblasts from the proband were detected by immunohistochemistry and western blotting. A 28-year-old male proband and his brother experienced recurrent stroke, hair loss and low back pain. Abnormalities in the proband were found in the elastic plate of subcutaneous small arteries, and a novel homozygous frameshift mutation (c.161_162insAG), leading to the formation of a stop codon 159 amino acids downstream of the insertion (p.Gly56Alafs*160) was detected. Reduced HTRA1 protein and increased TGF-β1 expression were detected in subcutaneous tissue and in cultured fibroblasts. A frameshift mutation in the HTRA1 gene detected in a CARASIL pedigree resulted in reduced HTRA1 protein and increased TGF-β1 expression, which may cause severe CARASIL and peripheral small arterial disease.

Heterozygous mutations of HTRA1 gene in patients with familial cerebral small vessel disease

“…Infarcts and Leukoencephalopathy (CARASIL) 7-9 is a very rare autosomal recessive familial SVD reported, with the exception of few cases, [10][11][12][13][14][15] only in a small number of Japanese and Chinese families.…”

“…Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL) is a very rare autosomal recessive familial SVD reported, with the exception of few cases, only in a small number of Japanese and Chinese families. CARASIL distinctive features include the onset in early adulthood (20‐30 years) of a nonhypertensive cerebral arteriopathy with rapidly progressive cognitive and motor disability in association with extraneurological manifestations, namely alopecia and spondylosis.…”

Loss of HtrA1 serine protease induces synthetic modulation of aortic vascular smooth muscle cells

“…The extensive VSMC loss and reduction in ECM proteins such as fibrillar collagens and fibronectin seem to be the primary abnormalities in CARASIL [ 28 ]. Small arteries in tissues other than the brain are also affected mildly [ 26 , 29 ]. Heterozygous mutations of HTRA1 were recently reported in a late-onset familial SVD group [ 30 ].…”

Histopathologic features of an autopsied patient with cerebral small vessel disease and a heterozygous HTRA1 mutation

“…5,10,11 However, these histological characteristics of the extracranial vessels appear to be quite different from those of intracranial small vessels. In contrast, patients with CARASIL show marked narrowing of the vascular lumen, atherosclerosis-like intimal thickening and arteriolosclerosis in the arteries of visceral organs and skin.…”

“…In contrast, patients with CARASIL show marked narrowing of the vascular lumen, atherosclerosis-like intimal thickening and arteriolosclerosis in the arteries of visceral organs and skin. 5,10,11 However, these histological characteristics of the extracranial vessels appear to be quite different from those of intracranial small vessels. Furthermore, it seems unlikely that these features are clearly distinct from athero-and arteriolosclerosis.…”