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HTRA1 expression profile and activity on TGF‐β signaling in HTRA1 mutation carriers
Author(s) -
Fasano Alessandro,
Formichi Patrizia,
Taglia Ilaria,
Bianchi Silvia,
Di Donato Ilaria,
Battisti Carla,
Federico Antonio,
Dotti Maria Teresa
Publication year - 2020
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.29609
Subject(s) - mutation , biology , missense mutation , phenotype , transforming growth factor , signal transduction , heterozygote advantage , gene knockdown , genetics , microbiology and biotechnology , gene , cancer research , allele
High temperature requirement A1 (HTRA1) is a serine protease playing a modulatory role in various cell processes, particularly in the regulation of transforming growth factor‐β (TGF‐β) signaling. A deleterious role in late‐onset cerebral small vessel diseases (CSVDs) of heterozygous HTRA1 mutations, otherwise causative in homozygosity of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, was recently suggested. However, the pathomechanism of these heterozygous mutations is still undefined. Our aim is to evaluate the expression profile and activity of HTRA1 on TGF‐β signaling in fibroblasts from four subjects carrying the HTRA1 heterozygous mutations—p.E42Dfs*173, p.A321T, p.G295R, and p.Q151K. We found a 50% reduction of HTRA1 expression in HTRA1 mutation carriers compared to the control. Moreover, we showed no changes in TGF‐β signaling pathway downstream intermediate, Phospho Smad2/3. However, we found overexpression of genes involved in the extracellular matrix formation in two heterozygous HTRA1 carriers. Our results suggest that each heterozygous HTRA1 missense mutation displays a different and peculiar HTRA1 expression pattern and that CSVD phenotype may also result from 50% of HTRA1 expression.