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Brain. 2015 Aug;138(Pt 8):2347-58. doi: 10.1093/brain/awv155. Epub 2015 Jun 10.

Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease.

Author information

1
1 INSERM UMR 1161, Génétique et Physiopathologie des Maladies Cérébro-vasculaires, Paris, France 2 Université Paris Diderot, Sorbonne Paris Cité, UMR-S1161, Paris, France.
2
1 INSERM UMR 1161, Génétique et Physiopathologie des Maladies Cérébro-vasculaires, Paris, France 2 Université Paris Diderot, Sorbonne Paris Cité, UMR-S1161, Paris, France 3 AP-HP, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Service de Neurologie, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'Oeil (CERVCO), Paris, France.
3
4 Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig Maximilians University, Munich, Germany.
4
5 AP-HP, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Service de Génétique Moléculaire Neurovasculaire, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'Oeil (CERVCO), Paris, France.
5
6 Service de Neurophysiologie, Hôpital Charles Nicolle, Rouen, France.
6
7 Service de Neurologie, Hôpital Gui de Chauliac, Montpellier, France.
7
8 Plateforme de Génomique Constitutionnelle du GHU Nord, Assistance Publique des Hôpitaux de Paris (APHP), Hôpital Bichat, Paris, France.
8
1 INSERM UMR 1161, Génétique et Physiopathologie des Maladies Cérébro-vasculaires, Paris, France 2 Université Paris Diderot, Sorbonne Paris Cité, UMR-S1161, Paris, France 5 AP-HP, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Service de Génétique Moléculaire Neurovasculaire, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'Oeil (CERVCO), Paris, France.
9
9 Service de Neurologie, CH Bretagne Sud, Lorient, France.
10
1 INSERM UMR 1161, Génétique et Physiopathologie des Maladies Cérébro-vasculaires, Paris, France.
11
4 Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig Maximilians University, Munich, Germany 1 INSERM UMR 1161, Génétique et Physiopathologie des Maladies Cérébro-vasculaires, Paris, France.
12
1 INSERM UMR 1161, Génétique et Physiopathologie des Maladies Cérébro-vasculaires, Paris, France 2 Université Paris Diderot, Sorbonne Paris Cité, UMR-S1161, Paris, France 5 AP-HP, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Service de Génétique Moléculaire Neurovasculaire, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'Oeil (CERVCO), Paris, France tournier-lasserve@univ-paris-diderot.fr.

Abstract

Cerebral small vessel disease represents a heterogeneous group of disorders leading to stroke and cognitive impairment. While most small vessel diseases appear sporadic and related to age and hypertension, several early-onset monogenic forms have also been reported. However, only a minority of patients with familial small vessel disease carry mutations in one of known small vessel disease genes. We used whole exome sequencing to identify candidate genes in an autosomal dominant small vessel disease family in which known small vessel disease genes had been excluded, and subsequently screened all candidate genes in 201 unrelated probands with a familial small vessel disease of unknown aetiology, using high throughput multiplex polymerase chain reaction and next generation sequencing. A heterozygous HTRA1 variant (R166L), absent from 1000 Genomes and Exome Variant Server databases and predicted to be deleterious by in silico tools, was identified in all affected members of the index family. Ten probands of 201 additional unrelated and affected probands (4.97%) harboured a heterozygous HTRA1 mutation predicted to be damaging. There was a highly significant difference in the number of likely deleterious variants in cases compared to controls (P = 4.2 × 10(-6); odds ratio = 15.4; 95% confidence interval = 4.9-45.5), strongly suggesting causality. Seven of these variants were located within or close to the HTRA1 protease domain, three were in the N-terminal domain of unknown function and one in the C-terminal PDZ domain. In vitro activity analysis of HTRA1 mutants demonstrated a loss of function effect. Clinical features of this autosomal dominant small vessel disease differ from those of CARASIL and CADASIL by a later age of onset and the absence of the typical extraneurological features of CARASIL. They are similar to those of sporadic small vessel disease, except for their familial nature. Our data demonstrate that heterozygous HTRA1 mutations are an important cause of familial small vessel disease, and that screening of HTRA1 should be considered in all patients with a hereditary small vessel disease of unknown aetiology.

KEYWORDS:

CADASIL; CARASIL; HTRA1; small vessel disease; vascular dementia

PMID:
26063658
DOI:
10.1093/brain/awv155
[Indexed for MEDLINE]

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