Characterization of Heterozygous <i>HTRA1</i> Mutations in Taiwanese Patients With Cerebral Small Vessel Disease.

Abstract

Homozygous and compound heterozygous mutations in the high temperature requirement serine peptidase A1 gene (<i>HTRA1</i>) cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. However, heterozygous <i>HTRA1</i> mutations were recently identified to be associated with autosomal dominant cerebral small vessel disease (SVD). The present study aims at investigating the clinical features, frequency, and spectrum of <i>HTRA1</i> mutations in a Taiwanese cohort with SVD. Mutational analyses of <i>HTRA1</i> were performed by Sanger sequencing in 222 subjects, selected from a cohort of 337 unrelated patients with SVD after excluding those harboring a <i>NOTCH3</i> mutation. The influence of these mutations on HTRA1 protease activities was characterized. Seven novel heterozygous mutations in <i>HTRA1</i> were identified, including p.Gly120Asp, p.Ile179Asn, p.Ala182Profs*33, p.Ile256Thr, p.Gly276Ala, p.Gln289Ter, and p.Asn324Thr, and each was identified in 1 single index patient. All mutations significantly compromise the HTRA1 protease activities. For the 7 index cases and another 2 affected siblings carrying a heterozygous <i>HTRA1</i> mutation, the common clinical presentations include lacunar infarction, intracerebral hemorrhage, cognitive decline, and spondylosis at the fifth to sixth decade of life. Among the 9 patients, 4 have psychiatric symptoms as delusion, depression, and compulsive behavior, 3 have leukoencephalopathy in anterior temporal poles, and 2 patients have alopecia. Heterozygous <i>HTRA1</i> mutations account for 2.08% (7 of 337) of SVD in Taiwan. The clinical and neuroradiological features of <i>HTRA1</i>-related SVD and sporadic SVD are similar. These findings broaden the mutational spectrum of <i>HTRA1</i> and highlight the pathogenic role of heterozygous <i>HTRA1</i> mutations in SVD.