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MAP3K6 Mutations in a Neurovascular Disease Causing Stroke, Cognitive Impairment, and Tremor

Ilinca, Andreea LU ; Englund, Elisabet LU orcid ; Samuelsson, Sofie LU ; Truvé, Katarina ; Kafantari, Efthymia LU ; Martinez-Majander, Nicolas ; Putaala, Jukka ; Håkansson, Claes LU ; Lindgren, Arne G LU and Puschmann, Andreas LU (2021) In Neurology: Genetics 7(1).
Abstract

Objective: To describe a possible novel genetic mechanism for cerebral small vessel disease (cSVD) and stroke.

Methods: We studied a Swedish kindred with ischemic stroke and intracerebral hemorrhage, tremor, dysautonomia, and mild cognitive decline. Members were examined clinically, radiologically, and by histopathology. Genetic workup included whole-exome sequencing (WES) and whole-genome sequencing (WGS) and intrafamilial cosegregation analyses.

Results: Fifteen family members were examined clinically. Twelve affected individuals had white matter hyperintensities and 1 or more of (1) stroke episodes, (2) clinically silent lacunar ischemic lesions, and (3) cognitive dysfunction. All affected individuals had tremor and/or... (More)

Objective: To describe a possible novel genetic mechanism for cerebral small vessel disease (cSVD) and stroke.

Methods: We studied a Swedish kindred with ischemic stroke and intracerebral hemorrhage, tremor, dysautonomia, and mild cognitive decline. Members were examined clinically, radiologically, and by histopathology. Genetic workup included whole-exome sequencing (WES) and whole-genome sequencing (WGS) and intrafamilial cosegregation analyses.

Results: Fifteen family members were examined clinically. Twelve affected individuals had white matter hyperintensities and 1 or more of (1) stroke episodes, (2) clinically silent lacunar ischemic lesions, and (3) cognitive dysfunction. All affected individuals had tremor and/or atactic gait disturbance. Mild symmetric basal ganglia calcifications were seen in 3 affected members. Postmortem examination of 1 affected member showed pathologic alterations in both small and large arteries the brain. Skin biopsies of 3 affected members showed extracellular amorphous deposits within the subepidermal zone, which may represent degenerated arterioles. WES or WGS did not reveal any potentially disease-causing variants in known genes for cSVDs or idiopathic basal ganglia calcification, but identified 1 heterozygous variant, NM_004672.4 MAP3K6 c.322G>A p.(Asp108Asn), that cosegregated with the disease in this large family. MAP3K6 has known functions in angiogenesis and affects vascular endothelial growth factor expression, which may be implicated in cerebrovascular disease.

Conclusions: Our data strongly suggest the MAP3K6 variant to be causative for this novel disease phenotype, but the absence of functional data and the present lack of additional families with this disease and MAP3K6 mutations still limit the formal evidence for the variant's pathogenicity.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Neurology: Genetics
volume
7
issue
1
article number
e548
publisher
Lippincott Williams & Wilkins
external identifiers
  • pmid:33728376
  • scopus:85114288152
ISSN
2376-7839
DOI
10.1212/NXG.0000000000000548
language
English
LU publication?
yes
id
0ee4c55d-79e7-4d5d-96e7-4a34f2c94762
date added to LUP
2021-08-16 10:08:48
date last changed
2022-08-11 23:13:36
@article{0ee4c55d-79e7-4d5d-96e7-4a34f2c94762,
  abstract     = {{<p>Objective: To describe a possible novel genetic mechanism for cerebral small vessel disease (cSVD) and stroke.</p><p>Methods: We studied a Swedish kindred with ischemic stroke and intracerebral hemorrhage, tremor, dysautonomia, and mild cognitive decline. Members were examined clinically, radiologically, and by histopathology. Genetic workup included whole-exome sequencing (WES) and whole-genome sequencing (WGS) and intrafamilial cosegregation analyses.</p><p>Results: Fifteen family members were examined clinically. Twelve affected individuals had white matter hyperintensities and 1 or more of (1) stroke episodes, (2) clinically silent lacunar ischemic lesions, and (3) cognitive dysfunction. All affected individuals had tremor and/or atactic gait disturbance. Mild symmetric basal ganglia calcifications were seen in 3 affected members. Postmortem examination of 1 affected member showed pathologic alterations in both small and large arteries the brain. Skin biopsies of 3 affected members showed extracellular amorphous deposits within the subepidermal zone, which may represent degenerated arterioles. WES or WGS did not reveal any potentially disease-causing variants in known genes for cSVDs or idiopathic basal ganglia calcification, but identified 1 heterozygous variant, NM_004672.4 MAP3K6 c.322G&gt;A p.(Asp108Asn), that cosegregated with the disease in this large family. MAP3K6 has known functions in angiogenesis and affects vascular endothelial growth factor expression, which may be implicated in cerebrovascular disease.</p><p>Conclusions: Our data strongly suggest the MAP3K6 variant to be causative for this novel disease phenotype, but the absence of functional data and the present lack of additional families with this disease and MAP3K6 mutations still limit the formal evidence for the variant's pathogenicity.</p>}},
  author       = {{Ilinca, Andreea and Englund, Elisabet and Samuelsson, Sofie and Truvé, Katarina and Kafantari, Efthymia and Martinez-Majander, Nicolas and Putaala, Jukka and Håkansson, Claes and Lindgren, Arne G and Puschmann, Andreas}},
  issn         = {{2376-7839}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Lippincott Williams & Wilkins}},
  series       = {{Neurology: Genetics}},
  title        = {{MAP3K6 Mutations in a Neurovascular Disease Causing Stroke, Cognitive Impairment, and Tremor}},
  url          = {{http://dx.doi.org/10.1212/NXG.0000000000000548}},
  doi          = {{10.1212/NXG.0000000000000548}},
  volume       = {{7}},
  year         = {{2021}},
}