HTRA1 – Autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy, type 2

Heterozygous variants in HTRA1 have been implicated in an autosomal dominant form of cerebral small vessel disease, termed CADASIL2, characterized by recurrent subcortical strokes, progressive leukoencephalopathy, and microhemorrhages. Unlike biallelic HTRA1 mutations causing CARASIL, monoallelic loss-of-function variants confer disease risk with incomplete penetrance and later onset (PMID:34510819).

Genetic evidence includes an index family in which a heterozygous HTRA1 c.497G>A (p.Arg166His) variant segregated with disease in three affected relatives (PMID:26063658), and subsequent screening of 201 unrelated probands identified ten additional carriers of predicted damaging HTRA1 variants. A separate cohort of four monoallelic carriers presented with recurrent strokes (mean age 51 years) and radiologic leukoencephalopathy (PMID:34510819).

The variant spectrum comprises missense substitutions within the protease domain (e.g., c.497G>A (p.Arg166His)), nonsense and frameshift alleles, and splice-site changes, indicating both catalytic and structural disruption. No founder variants have been reported to date, and allele frequencies are absent or extremely low in population databases.

Functional studies demonstrate that CADASIL2-associated HTRA1 mutants exhibit reduced proteolytic activity, fail to repress transforming growth factor-β signaling, and display altered secretion or stability in vitro, consistent with a loss-of-function mechanism (PMID:26063658). These findings align with haploinsufficiency models and support pathogenicity of monoallelic HTRA1 variants.

A targeted next-generation sequencing study of 70 CADASIL-like patients found no pathogenic HTRA1 mutations, underscoring locus heterogeneity and the need for comprehensive gene panels in small vessel disease diagnostics (PMID:25929831).

Overall, strong genetic and moderate functional evidence link heterozygous HTRA1 variants to CADASIL2. While additional pedigrees continue to be reported, current data support inclusion of HTRA1 in diagnostic testing for familial adult‐onset small vessel disease.

Key take-home: Heterozygous HTRA1 loss-of-function variants cause autosomal dominant CADASIL2, warranting genetic screening in familial small vessel disease with subcortical infarcts and leukoencephalopathy.

References

• Molecular Genetics & Genomic Medicine • 2021 • Clinicoradiographic and genetic features of cerebral small vessel disease indicate variability in mode of inheritance for monoallelic HTRA1 variants. PMID:34510819
• Brain : a journal of neurology • 2015 • Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease. PMID:26063658
• Journal of molecular neuroscience : MN • 2015 • A Next-Generation Sequencing of the NOTCH3 and HTRA1 Genes in CADASIL Patients. PMID:25929831

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