HTRA1 expression profile and activity on TGF‐β signaling in HTRA1 mutation carriers

• Published in: Journal of cellular physiology Vol. 235; no. 10; pp. 7120 - 7127
• Main Authors: Fasano, Alessandro, Formichi, Patrizia, Taglia, Ilaria, Bianchi, Silvia, Di Donato, Ilaria, Battisti, Carla, Federico, Antonio, Dotti, Maria Teresa
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.10.2020
• Subjects: Alopecia - genetics; Alopecia - metabolism; Blood vessels; CARASIL; Cells, Cultured; Cerebral Infarction - genetics; Cerebral Infarction - metabolism; cerebral small vessel diseases; Cerebrovascular Disorders - genetics; Cerebrovascular Disorders - metabolism; Extracellular matrix; Female; Fibroblasts; Fibroblasts - metabolism; Growth factors; Heterozygote; High temperature; High-Temperature Requirement A Serine Peptidase 1 - genetics; High-Temperature Requirement A Serine Peptidase 1 - metabolism; Homozygosity; HTRA1 expression; HTRA1 heterozygous mutations; Humans; Kinases; Leukoencephalopathies - genetics; Leukoencephalopathies - metabolism; Leukoencephalopathy; Male; Middle Aged; Missense mutation; Mutation; Phenotypes; Serine; Serine proteinase; Signal Transduction; Signaling; Smad2 protein; Spinal Diseases - genetics; Spinal Diseases - metabolism; Temperature requirements; Transcriptome; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; HTRA1 heterozygous mutations; cerebral small vessel diseases; HTRA1 expression; CARASIL
• ISSN: 0021-9541; 1097-4652; 1097-4652
• DOI: 10.1002/jcp.29609

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. We found a 50% reduction of high temperature requirement A1 (HTRA1) expression in HTRA1 mutation carriers compared to the control. Moreover, we showed no changes in transforming growth factor‐β (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.