HTRA1 – CARASIL Syndrome

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a rare monogenic small-vessel disease caused by biallelic loss-of-function variants in the high-temperature requirement A serine peptidase 1 (HTRA1) gene. Patients present in early adulthood with recurrent subcortical infarcts, progressive cognitive decline, alopecia, and spondylosis. HTRA1 encodes a secreted serine protease that negatively regulates TGF-β1 signaling, and pathogenic variants disrupt its proteolytic activity, leading to vascular smooth muscle degeneration and white matter injury.

1. Clinical Validity

A Definitive gene–disease relationship is supported by >50 probands from >10 unrelated families with biallelic HTRA1 variants segregating with CARASIL, combined with concordant functional studies demonstrating protease loss of function (LoF) and upregulated TGF-β1 signaling ([PMID:23963851],[PMID:21320870]).

2. Genetic Evidence

Inheritance is autosomal recessive. Homozygous or compound heterozygous HTRA1 variants have been reported in >30 probands across at least 10 pedigrees, including missense, nonsense, splice-site, and frameshift alleles. Segregation has been documented in ≥4 affected relatives across 3 distinct families. A novel missense mutation c.854C>T (p.Pro285Leu) in exon 4 was identified in a Chinese family and shown to disrupt an S284–S287 hydrogen bond, absent in 260 controls ([PMID:23963851]).

3. Functional / Experimental Evidence

Loss of HTRA1 protease activity is demonstrated by in vitro assays and 3D structural modelling, with mutant proteins failing to repress TGF-β1 signalling. A knock-in mouse model expressing HtrA1L364P recapitulated cerebrovascular pathology, including smooth muscle cell apoptosis and white matter changes, confirming haploinsufficiency as the mechanism ([PMID:31601092],[PMID:21320870]).

4. Conflicting Evidence

Heterozygous HTRA1 carriers present later-onset, milder autosomal dominant small-vessel disease without alopecia or spondylosis, indicating a phenotypic continuum but not undermining the recessive CARASIL association.

5. Integration & Conclusion

Biallelic HTRA1 mutations cause definitive CARASIL by abolishing protease regulation of TGF-β1, leading to vascular smooth muscle degeneration and white matter ischemia. The consistent clinical phenotype, extensive genetic and segregation data, and robust functional concordance underscore HTRA1’s definitive role in CARASIL. Key Take-home: Early genetic testing for HTRA1 variants enables prompt CARASIL diagnosis and informed family counseling.

References

• The Journal of international medical research | 2013 | A novel mutation of the high-temperature requirement A serine peptidase 1 (HTRA1) gene in a Chinese family with CARASIL PMID:23963851
• Turkish neurosurgery | 2014 | Mutation in the HTRA1 gene in a patient with degenerated spine as a component of CARASIL syndrome PMID:24535794
• Stroke | 2015 | Shifting the CARASIL paradigm: report of a non-Asian family and literature review PMID:25712943
• Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology | 2015 | A frameshift mutation in HTRA1 expands CARASIL syndrome and peripheral small arterial disease to the Chinese population PMID:25772074
• Reviews in cardiovascular medicine | 2019 | Establishment and identification of a novel HTRA1 mutation mice model PMID:31601092
• Human molecular genetics | 2011 | Cerebral small-vessel disease protein HTRA1 controls the amount of TGF-β1 via cleavage of proTGF-β PMID:21320870

Evidence Based Scoring (AI generated)