Heterozygous Pathogenic and Likely Pathogenic Symptomatic HTRA1 Variant Carriers in Cerebral Small Vessel Disease

Abstract

High temperature requirement serine peptidase A1 (HTRA1) related cerebral small vessel disease (CSVD) includes both symptomatic heterozygous HTRA1 variant carrier and cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) patients. Presently, most reported symptomatic heterozygous HTRA1 variant carrier cases are sporadic family reports with a lack of specific characteristics. Additionally, the molecular mechanism of heterozygous HTRA1 gene variants is unclear. We conducted this review to collect symptomatic carriers of heterozygous HTRA1 gene variants reported as of 2022, analyzed all pathogenicity according to American College of Medical Genetics and Genomics (ACMG) variant classification, and summarized the cases with pathogenic and likely pathogenic HTRA1 variants gender characteristics, age of onset, geographical distribution, initial symptoms, clinical manifestations, imaging signs, HTRA1 gene variant information and to speculate its underlying pathogenic mechanisms. In this review, we summarized the following characteristics of pathogenic and likely pathogenic symptomatic HTRA1 variant carriers: to date, the majority of reported symptomatic HTRA1 carriers are in European and Asian countries, particularly in China which was found to have the highest number of reported cases. The age of first onset is mostly concentrated in the fourth and fifth decades. The heterozygous HTRA1 gene variants were mostly missense variants. The two variant sites, 166–182 aa and 274–302 aa, were the most concentrated. Clinicians need to pay attention to de novo data and functional data, which may affect the pathogenicity analysis. The decrease in HtrA1 protease activity is currently the most important explanation for the genetic pathogenesis.

Exploring HTRA1-Autosomal Dominant Disease: Literature Review of Clinical Features and Molecular Mechanisms

“…However, contradictory evidence has emerged suggesting that HTRA1 protease can increase TGF-β release and signaling (Beaufort et al, 2014). It has been suggested that TGF-β participates in various pathogenic mechanisms in CARASIL (Xu et al, 2023;Yamamoto & Ihara, 2017), while the precise role of TGF-β in heterozygous HTRA1-related disease requires further investigation.…”

“…Clinical manifestations of HTRA1-autosomal dominant disease include stroke, cognitive decline, gait disorders, psychiatric disorders, alopecia, migraine, and spine disorders. The first symptom of onset is mostly stroke (45%) (Xu et al, 2023). Extra-neurological features are less common, with spine disorders present in 47.27% and alopecia in 20% of cases.…”

“…The mutations are mostly clustered in exon 4 (~50%) (He et al, 2023). Missense mutations are commonly localized in the linker region or the protease domain, particularly affecting the L3/LD loops (Xu et al, 2023), whereas stop-gain mutations are more widely distributed across the gene (Coste et al, 2021). One plausible explanation for the aggregation in L3/LD and the linker region is that these regions are significant in enzyme activities.…”

“…Of note, hereditary cSVDs should not be excluded even when patients are present with vascular risk factors and no significant familial history(Mancuso et al, 2020). The American College of Medical Genetics and Genomics (ACMG) guidelines should serve as a crucial reference for assessing the pathogenicity of mutations(Xu et al, 2023). While effective treatments are currently unavailable, the management of vascular risk factors holds potential significance in preventing the onset and progression of the disease in heterozygous mutation carriers(Grigaitė et al, 2021).…”