Annals of Indian Academy of Neurology
  Users Online: 1479 Home | About the Journal | InstructionsCurrent Issue | Back IssuesLogin      Print this page Email this page  Small font size Default font size Increase font size

Table of Contents
LETTER TO THE EDITOR
Year : 2020  |  Volume : 23  |  Issue : 6  |  Page : 832-835
 

Novel heterozygous HTRA1 pathogenic variant found in a Chinese family with autosomal dominant cerebral small vessel Disease


1 Department of Neurology, Taizhou Hospital, Affiliated Hospital of Wenzhou Medical University, Taizhou, Zhejiang, PR China
2 Department of General Surgery, The First People's Hospital of Linhai, Taizhou, Zhejiang, PR China
3 Shaofa Ke Department of Neurology, Taizhou Hospital, Affiliated Hospital of Wenzhou Medical University, Taizhou, Zhejiang, PR China

Date of Submission06-Feb-2020
Date of Decision09-Apr-2020
Date of Acceptance26-Apr-2020
Date of Web Publication07-Oct-2020

Correspondence Address:
Dr. Shaofa Ke
Department of Neurology, Taizhou Hospital, Affiliated Hospital of Wenzhou Medical University. Ximen Road, 150#, Taizhou, Zhejiang - 317000
PR China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aian.AIAN_74_20

Rights and Permissions

 



How to cite this article:
Wu C, Chen L, Ke S. Novel heterozygous HTRA1 pathogenic variant found in a Chinese family with autosomal dominant cerebral small vessel Disease. Ann Indian Acad Neurol 2020;23:832-5

How to cite this URL:
Wu C, Chen L, Ke S. Novel heterozygous HTRA1 pathogenic variant found in a Chinese family with autosomal dominant cerebral small vessel Disease. Ann Indian Acad Neurol [serial online] 2020 [cited 2021 Jan 21];23:832-5. Available from: https://www.annalsofian.org/text.asp?2020/23/6/832/297446




Sir,

Cerebral small vessel disease (CSVD) represents a heterogeneous group of disorders leading to stroke and cognitive impairment. Although most of the cases are sporadic, familial monogenic causes have been identified in a growing minority of patients. CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy), linked to high temperature requirement protease A1 (HTRA1) gene mutations is a rare but well-known autosomal recessive CSVD. Recently, heterozygous HTRA1 mutations have been described in patients with autosomal dominant CSVD. Here, we report two autosomal dominant cases in a Chinese family with a novel p.Val279Glu (c.836T > A) mutation in HTRA1 gene.

Cerebral small vessel disease (CSVD) is a heterogeneous group of disorders affecting small arteries, arterioles, veins, and/or capillaries of the brain.[1] It is commonly recognized to be the leading cause of vascular cognitive impairment. Besides the common sporadic forms, mostly related to age and hypertension, a minority of CSVD has a monogenic cause, and most of them have a dominant inheritance pattern.[2]

CARASIL is a rare form of autosomal recessive CSVD. Biallelic mutations of the HTRA1 (high temperature requirement protease A1) were the only identified reason for CARASIL.[3] Recently, heterozygous HTRA1 mutations were also reported associated with autosomal dominant CSVD.[4] In this study, two patients from a Chinese family with clinical data suggestive of autosomal dominant CVSD were investigated. We found a novel heterozygous p.Val279Glu (c.836T >A) mutation in HTRA1 gene, with negative NOTCH3 mutations.

The genealogical tree of the family is shown in [Figure 1]. The proband (II3) is a 51-year-old male who is a government worker with no vascular risk factor, such as hypertension, diabetes mellitus, atrial fibrillation, or smoking. At age 45 he experienced an acute episode of left-sided hemiparesis, which completely resolved in about one week. Since then, he has suffered two more minor ischemic strokes (National Institute of Health stroke scale score ≤ 3) at the ages of 49 and 50. Since age 49 he complained of progressive impairment of work performance and recent memory decline, especially the text dictation ability. He did not have alopecia, migraine, spondylopathy, and retinal dysfunctions. Neuropsychological testing revealed mild alterations in processing speed, executive functions, and verbal episodic and visuospatial memory performances suggestive of subcortical cognitive impairment. Mini-Mental State Examination score was 24/30. Montreal Cognitive Assessment was 23/30. Computed tomography angiography of cervical and brain arteries showed no obvious arteriostenosis. Blood cell count, antinuclear antibody, thyroid function, and other fundus examination were normal. Brain magnetic resonance image (MRI)[Figure 2] showed multifocal cerebral infarction and extensive cerebral white matter lesions. Areas of encephalomalacia, likely the sequelae of remote lacunar infarcts, were seen in the right hemisphere. Diffuse white matter abnormalities were seen in the supratentorial white matter, corpus callosum, and basal ganglia region, but sparing the anteroinferior temporal lobes. Several microbleeds were detected on susceptibility weighted images.
Figure 1: Pedigrees of the probands. Square = male; circle = female; diagonal black line = deceased individual; black filled symbol = clinically and MRI proven affected individual, showing an HTRA1 deleterious variant; empty symbol = clinically healthy and HTRA1 negative relative; black dot = affected individual based on clinical charts; question mark = unknown status

Click here to view
Figure 2: MRI images of proband and II-1. Left three columns: Proband at the age of 45, 48, 51. Right column: II-1 at the age of 55. First line: T2-weighted images. Second line: FLAIR images. Third line: T1-weighted image (A 45y), 3D time of flight image (A 48y, B 55y), gradient-echo image (A 51y). Multifocal cerebral infarction (yellow arrow). White matter hyperintensities (white arrow) involve corona radiata, bilateral periventricular and corpus callosum. Microbleeds (red arrow). No atherostenosis are detected

Click here to view


His elder brother (II-1) has been suffered a cerebral lacunar infarction with right-sided hemiparesis two years ago. MRI [Figure 2] also shows several subcortical lacunar infarcts and high intensities in the corona radiate, and bilateral periventricular white matter did not show specific signal abnormalities at the temporal pole or basal ganglia. He has not yet shown signs of dementia. His father (I-1) had a history of recent memory impairment, slowness of mental processes for about five years, and died of cerebral hemorrhage at the age of 72. His head CT reports white matter degeneration in addition to right temporal lobe hemorrhage. Unfortunately, we did not find imaging data. His mother (I-2) died of cardiogenic cerebral embolismat the age of 80 with no obvious cognitive impairment.

Genetic analysis of hundreds of leukoencephalopathy related genes by targeted next-generation sequencing (NGS) in the probrevealed a novel heterozygous missense mutation [Figure 3], p.Val279Glu (c.836T>A), in exon4 of HTRA1, which is located in serine protease domain. In silico analysis with PolyPhen-2 and sorting intolerant from tolerant (SIFT) all revealed the mutation to be deleterious. The mutation was not found in the 1000 Genomes database, ClinVar, and our in-house database (including 300 next-generation sequencing samples). The proband's elder brother (II-1) also carried the mutation. The rest family members (II-2, II-4, II-5, III-1) without any neurological symptoms were negative for this variant. Therefore, we believe this HTRA1 variant as a pathogenic mutation in the family.
Figure 3: Sequence diagram of heterozygous HTRA1 c. 836T > A mutation in the (a) proband (II-3) and (b) his elder brother (II-1)

Click here to view


HTRA1 in the etiology of CSVD was first described in Japanese consanguineous families of CARASIL,[4] based on the disorder's recessive inheritance and resemblance to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Recent studies[5],[6] demonstrated that heterozygous HTRA1 mutations were also associated with autosomal dominant hereditary CSVD. Compare to CADASIL and CARASIL, these studies found in heterozygous HTRA1, the clinical symptoms (mostly subcortical ischemic events and cognitive decline) is milder, the age of onset is older (usually in the sixth decade), the history of illness is long-lasting, extra-neurological signs and migraine are lacking. Brain MRI showed confluent white matter hyper-intensities on MRI T2-weighted and FLAIR images, spared anterior temporal regions and U fibers. However, the hyperintensities of white matter on MRI were less severe than in CADASIL or CARASIL. We reported two cases with the same heterozygous HTRA1 mutation, which segregates as an autosomal dominant disorder. The phenotype and MRI features of our cases are consistent with previous reports. Of note, we found corpus callosum involvement in the proband's brain MRI, which is a finding rarely observed in CADASIL, CARASIL, and sporadic CSVD. Donato et al.[6] had also reported one heterozygous HTRA1 mutation case with leukoencephalopathy involving corpus callosum. At the same time, we exhibit the changing of the proband's brain MRI from the first stroke, and we found the white matter hyper-intensities kept stable in the first three years, but increased when he had the symptoms of dementia, which provide a reference for future similar cases.

The HTRA1 gene located on chromosome 10q (10q25.3-q26.2) consists of 9 exons. HTRA1 has an N-terminal insulin-like growth factor–binding protein domain, a trypsin-like serine protease domain, a Kazal-type serine protease inhibitor domain, and a C-terminal PDZ domain.[7] HTRA1 is a gene that encodes a serine protease, which regulates insulin-like growth factor by cleaving the IGR binding protein. Nozaki et al. demonstrated that HTRA1 with heterozygote mutations have dominant-negative effects on wild-type HTRA1 protease activity due to its inability to form stable trimmers.[8] Truebestein et al.[9] found the trimerization of HTRA1 is mainly mediated by N-terminal residues of the protease domain: Tyr169, Phe171, and Phe278 of each monomer undergo ring stacking interactions to stabilize the trimer. The mutation V279G found in our patients is located near Phe278, which is a core residue for trimer formation.[9] A similar mechanism was observed in the dominant-negative effect exerted by the p.G278R receptor activator of nuclear factor kappa-B ligand (RANKL) variant. The G278R RANKL monomers failed to assemble into homotrimers and interact with wild-type RANKL, resulting in a dominant-negative effect on trimerization.[10] We speculate that the p.V279G mutation might interfere with the trimerization of wild-type HTRA 1in a similar manner.

We report two autosomal dominant CSVD cases in a Chinese family with a novel heterozygous p.Val279Glu (c.836T>A) mutation in HTRA1 gene. Therefore, we suggest performing the screening of HTRA1 in all patients with a familial CSVD when the extent of microvascular lesions on MRI contrasts with the paucity of vascular risk factors.

Declaration of patient consent

The Medical Ethics Committee of Taizhou Hospital approved the study and all participants provided written informed consent. In the form the patients have given their consent for their images and other clinical information to be reported in the journal.

Acknowledgements

We thank our patients for participating in this study. No financial support was received for our study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Wardlaw JM, Smith C, Dichgans M. Mechanisms of sporadic cerebral small vessel disease: Insights from neuroimaging. Lancet Neurol 2013;12:483-97.  Back to cited text no. 1
    
2.
Tan RYY, Markus HS. Monogenic causes of stroke: Now and the future. J Neurol2015;262:2601-6.  Back to cited text no. 2
    
3.
Hara K, Shiga A, Fukutake T, Nozaki H, Miyashita A, Yokoseki A, et al. Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. N Engl J Med 2009;360:1729-39.  Back to cited text no. 3
    
4.
Fukutake T, Hirayama K. Familial young-adult-onset arteriosclerotic leukoencephalopathy with alopecia and lumbago without arterial hypertension. Eur Neurol 1995;35:69-79.  Back to cited text no. 4
    
5.
Verdura E, Hervé D, Scharrer E, Amador Mdel M, Guyant-Maréchal L, Philippi A, et al. Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease. Brain 2015;138:2347-58.  Back to cited text no. 5
    
6.
Di Donato I, Bianchi S, Gallus GN, Cerase A, Taglia I, Pescini F, et al. Heterozygous mutations of HTRA1 gene in patients with familial cerebral small vessel disease. CNS Neurosci Ther2017;23:759-65.  Back to cited text no. 6
    
7.
Eigenbrot C, Ultsch M, Lipari MT, Moran P, Lin SJ, Ganesan R, et al. Structural and functional analysis of HtrA1 and its subdomains. Structure 2012;20:1040-50.  Back to cited text no. 7
    
8.
Nozaki H, Kato T, Nihonmatsu M. Distinct molecular mechanisms of HTRA1 mutants in manifesting heterozygotes with CARASIL. Neurology 2016;86:1964-74.  Back to cited text no. 8
    
9.
Truebestein L, Tennstaedt A, Mönig T, Krojer T, Canellas F, Kaiser M, et al. Substrate-induced remodeling of the active site regulates human HTRA1 activity. Nat Struct Mol Biol 2011;18:386-8.  Back to cited text no. 9
    
10.
Douni E, Rinotas V, Makrinou E, Zwerina J, Penninger JM, Eliopoulos E, et al. A RANKL G278R mutation causing osteopetrosis identifies a functional amino acid essential for trimer assembly in RANKL and TNF. Hum Mol Genet 2012;21:784-98.  Back to cited text no. 10
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

Top
Print this article  Email this article

    

 
   Search
 
  
    Similar in PUBMED
    Article in PDF (715 KB)
    Citation Manager
    Access Statistics
    Reader Comments
    Email Alert *
    Add to My List *
* Registration required (free)  


    References
    Article Figures

 Article Access Statistics
    Viewed186    
    Printed4    
    Emailed0    
    PDF Downloaded9    
    Comments [Add]    

Recommend this journal