Novel COL4A1 mutations cause cerebral small vessel disease by haploinsufficiency

R. Lemmens, A. Maugeri, H.W.M. Niessen, A. Goris, T. Tousseyn, P. Demaerel, A. Corveleyn, W. Robberecht, M.S. van der Knaap, V.N. Thijs, P.J.G. Zwijnenburg

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Mutations in COL4A1 have been identified in families with hereditary small vessel disease of the brain presumably due to a dominant-negative mechanism. Here, we report on two novel mutations in COL4A1 in two families with porencephaly, intracerebral hemorrhage and severe white matter disease caused by haploinsufficiency. Two families with various clinical presentations of cerebral microangiopathy and autosomal dominant inheritance were examined. Clinical, neuroradiological and genetic investigations were performed. Electron microscopy of the skin was also performed. In one of the families, sequence analysis revealed a one base deletion, c.2085del, leading to a frameshift and a premature stopcodon, p.(Gly696fs). In the other family, a splice site mutation was identified, c.2194-1G>A, which most likely leads to skipping of an exon with a frameshift and premature termination as a result. In fibroblasts of affected individuals from both the families, nonsense-mediated decay (NMD) of the mutant COL4A1 messenger RNAs (mRNAs) and a clear reduction of COL4A1 protein expression were demonstrated, indicating haploinsufficiency of COL4A1. Moreover, thickening of the capillary basement membrane in the skin was documented, similar to reports in patients with COL4A1 missense mutations. These findings suggest haploinsufficiency, a different mechanism from the commonly assumed dominant-negative effect, for COL4A1 mutations as a cause of (antenatal) intracerebral hemorrhage and white matter disease.

Original languageEnglish
Pages (from-to)391-397
Number of pages7
JournalHuman Molecular Genetics
Volume22
Issue number2
DOIs
Publication statusPublished - 15 Jan 2013

Cite this

Lemmens, R. ; Maugeri, A. ; Niessen, H.W.M. ; Goris, A. ; Tousseyn, T. ; Demaerel, P. ; Corveleyn, A. ; Robberecht, W. ; van der Knaap, M.S. ; Thijs, V.N. ; Zwijnenburg, P.J.G. / Novel COL4A1 mutations cause cerebral small vessel disease by haploinsufficiency. In: Human Molecular Genetics. 2013 ; Vol. 22, No. 2. pp. 391-397.
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abstract = "Mutations in COL4A1 have been identified in families with hereditary small vessel disease of the brain presumably due to a dominant-negative mechanism. Here, we report on two novel mutations in COL4A1 in two families with porencephaly, intracerebral hemorrhage and severe white matter disease caused by haploinsufficiency. Two families with various clinical presentations of cerebral microangiopathy and autosomal dominant inheritance were examined. Clinical, neuroradiological and genetic investigations were performed. Electron microscopy of the skin was also performed. In one of the families, sequence analysis revealed a one base deletion, c.2085del, leading to a frameshift and a premature stopcodon, p.(Gly696fs). In the other family, a splice site mutation was identified, c.2194-1G>A, which most likely leads to skipping of an exon with a frameshift and premature termination as a result. In fibroblasts of affected individuals from both the families, nonsense-mediated decay (NMD) of the mutant COL4A1 messenger RNAs (mRNAs) and a clear reduction of COL4A1 protein expression were demonstrated, indicating haploinsufficiency of COL4A1. Moreover, thickening of the capillary basement membrane in the skin was documented, similar to reports in patients with COL4A1 missense mutations. These findings suggest haploinsufficiency, a different mechanism from the commonly assumed dominant-negative effect, for COL4A1 mutations as a cause of (antenatal) intracerebral hemorrhage and white matter disease.",
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author = "R. Lemmens and A. Maugeri and H.W.M. Niessen and A. Goris and T. Tousseyn and P. Demaerel and A. Corveleyn and W. Robberecht and {van der Knaap}, M.S. and V.N. Thijs and P.J.G. Zwijnenburg",
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Novel COL4A1 mutations cause cerebral small vessel disease by haploinsufficiency. / Lemmens, R.; Maugeri, A.; Niessen, H.W.M.; Goris, A.; Tousseyn, T.; Demaerel, P.; Corveleyn, A.; Robberecht, W.; van der Knaap, M.S.; Thijs, V.N.; Zwijnenburg, P.J.G.

In: Human Molecular Genetics, Vol. 22, No. 2, 15.01.2013, p. 391-397.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Novel COL4A1 mutations cause cerebral small vessel disease by haploinsufficiency

AU - Lemmens, R.

AU - Maugeri, A.

AU - Niessen, H.W.M.

AU - Goris, A.

AU - Tousseyn, T.

AU - Demaerel, P.

AU - Corveleyn, A.

AU - Robberecht, W.

AU - van der Knaap, M.S.

AU - Thijs, V.N.

AU - Zwijnenburg, P.J.G.

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N2 - Mutations in COL4A1 have been identified in families with hereditary small vessel disease of the brain presumably due to a dominant-negative mechanism. Here, we report on two novel mutations in COL4A1 in two families with porencephaly, intracerebral hemorrhage and severe white matter disease caused by haploinsufficiency. Two families with various clinical presentations of cerebral microangiopathy and autosomal dominant inheritance were examined. Clinical, neuroradiological and genetic investigations were performed. Electron microscopy of the skin was also performed. In one of the families, sequence analysis revealed a one base deletion, c.2085del, leading to a frameshift and a premature stopcodon, p.(Gly696fs). In the other family, a splice site mutation was identified, c.2194-1G>A, which most likely leads to skipping of an exon with a frameshift and premature termination as a result. In fibroblasts of affected individuals from both the families, nonsense-mediated decay (NMD) of the mutant COL4A1 messenger RNAs (mRNAs) and a clear reduction of COL4A1 protein expression were demonstrated, indicating haploinsufficiency of COL4A1. Moreover, thickening of the capillary basement membrane in the skin was documented, similar to reports in patients with COL4A1 missense mutations. These findings suggest haploinsufficiency, a different mechanism from the commonly assumed dominant-negative effect, for COL4A1 mutations as a cause of (antenatal) intracerebral hemorrhage and white matter disease.

AB - Mutations in COL4A1 have been identified in families with hereditary small vessel disease of the brain presumably due to a dominant-negative mechanism. Here, we report on two novel mutations in COL4A1 in two families with porencephaly, intracerebral hemorrhage and severe white matter disease caused by haploinsufficiency. Two families with various clinical presentations of cerebral microangiopathy and autosomal dominant inheritance were examined. Clinical, neuroradiological and genetic investigations were performed. Electron microscopy of the skin was also performed. In one of the families, sequence analysis revealed a one base deletion, c.2085del, leading to a frameshift and a premature stopcodon, p.(Gly696fs). In the other family, a splice site mutation was identified, c.2194-1G>A, which most likely leads to skipping of an exon with a frameshift and premature termination as a result. In fibroblasts of affected individuals from both the families, nonsense-mediated decay (NMD) of the mutant COL4A1 messenger RNAs (mRNAs) and a clear reduction of COL4A1 protein expression were demonstrated, indicating haploinsufficiency of COL4A1. Moreover, thickening of the capillary basement membrane in the skin was documented, similar to reports in patients with COL4A1 missense mutations. These findings suggest haploinsufficiency, a different mechanism from the commonly assumed dominant-negative effect, for COL4A1 mutations as a cause of (antenatal) intracerebral hemorrhage and white matter disease.

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KW - Cerebral Small Vessel Diseases

KW - Collagen Type IV

KW - Female

KW - Fibroblasts

KW - Haploinsufficiency

KW - Humans

KW - Magnetic Resonance Imaging

KW - Male

KW - Middle Aged

KW - Mutation

KW - Pedigree

KW - Young Adult

KW - Case Reports

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

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DO - 10.1093/hmg/dds436

M3 - Article

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EP - 397

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

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