Pagnamenta, Alistair T., Kaiyrzhanov, Rauan ORCID: 0000-0003-1640-4010, Zou, Yaqun, Da'as, Sahar, I, Maroofian, Reza, Donkervoort, Sandra, Dominik, Natalia, Lauffer, Marlen ORCID: 0000-0003-1607-0428, Ferla, Matteo P., Orioli, Andrea, Giess, Adam, Tucci, Arianna, Beetz, Christian, Sedghi, Maryam, Ansari, Behnaz, Barresi, Rita ORCID: 0000-0001-7351-959X, Basiri, Keivan, Cortese, Andrea, Elgar, Greg, Fernandez-Garcia, Miguel A., Yip, Janice, Foley, A. Reghan, Gutowski, Nicholas, Jungbluth, Heinz ORCID: 0000-0002-7159-3427, Lassche, Saskia, Lavin, Tim, Marcelis, Carlo, Marks, Peter, Marini-Bettolo, Chiara, Medne, Livija, Moslemi, Ali-Reza, Sarkozy, Anna, Reilly, Mary M., Muntoni, Francesco, Millan, Francisca, Muraresku, Colleen C., Need, Anna C., Nemeth, Andrea H., Neuhaus, Sarah B., Norwood, Fiona, O'Donnell, Marie, O'Driscoll, Mary, Rankin, Julia, Yum, Sabrina W., Zolkipli-Cunningham, Zarazuela, Brusius, Isabell, Wunderlich, Gilbert, Karakaya, Mert, Wirth, Brunhilde ORCID: 0000-0003-4051-5191, Fakhro, Khalid A., Tajsharghi, Homa, Bonnemann, Carsten G., Taylor, Jenny C. and Houlden, Henry (2021). An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy. Brain, 144. S. 584 - 601. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2156

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Abstract

The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes a component of the extracellular matrix that interacts with perlecan/collagen VI, appears to be involved in stabilizing extracellular matrix structures, and demonstrates high expression levels in tibial nerve. Vwa1-deficient mice manifest with abnormal peripheral nerve structure/function; however, VWA1 variants have not previously been associated with human disease. By interrogating the genome sequences of 74 180 individuals from the 100K Genomes Project in combination with international gene-matching efforts and targeted sequencing, we identified 17 individuals from 15 families with an autosomal-recessive, non-length dependent, hereditary motor neuropathy and rare biallelic variants in VWA1. A single disease-associated allele p.(G25Rfs*74), a 10-bp repeat expansion, was observed in 14/15 families and was homozygous in 10/15. Given an allele frequency in European populations approaching 1/1000, the seven unrelated homozygote individuals ascertained from the 100K Genomes Project represents a substantial enrichment above expected. Haplotype analysis identified a shared 220 kb region suggesting that this founder mutation arose 47000 years ago. A wide age-range of patients (6-83 years) helped delineate the clinical phenotype over time. The commonest disease presentation in the cohort was an early-onset (mean 2.0 +/- 1.4 years) non-length-dependent axonal hereditary motor neuropathy, confirmed on electrophysiology, which will have to be differentiated from other predominantly or pure motor neuropathies and neuronopathies. Because of slow disease progression, ambulation was largely preserved. Neurophysiology, muscle histopathology, and muscle MRI findings typically revealed clear neurogenic changes with single isolated cases displaying additional myopathic process. We speculate that a few findings of myopathic changes might be secondary to chronic denervation rather than indicating an additional myopathic disease process. Duplex reverse transcription polymerase chain reaction and immunoblotting using patient fibroblasts revealed that the founder allele results in partial nonsense mediated decay and an absence of detectable protein. CRISPR and morpholino vwa1 modelling in zebrafish demonstrated reductions in motor neuron axonal growth, synaptic formation in the skeletal muscles and locomotive behaviour. In summary, we estimate that biallelic variants in VWA1 may be responsible for up to 1% of unexplained hereditary motor neuropathy cases in Europeans. The detailed clinical characterization provided here will facilitate targeted testing on suitable patient cohorts. This novel disease gene may have previously evaded detection because of high GC content, consequential low coverage and computational difficulties associated with robustly detecting repeat-expansions. Reviewing previously unsolved exomes using lower QC filters may generate further diagnoses.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Pagnamenta, Alistair T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaiyrzhanov, RauanUNSPECIFIEDorcid.org/0000-0003-1640-4010UNSPECIFIED
Zou, YaqunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Da'as, Sahar, IUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maroofian, RezaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Donkervoort, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dominik, NataliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lauffer, MarlenUNSPECIFIEDorcid.org/0000-0003-1607-0428UNSPECIFIED
Ferla, Matteo P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Orioli, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giess, AdamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tucci, AriannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beetz, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sedghi, MaryamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ansari, BehnazUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barresi, RitaUNSPECIFIEDorcid.org/0000-0001-7351-959XUNSPECIFIED
Basiri, KeivanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cortese, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Elgar, GregUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fernandez-Garcia, Miguel A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yip, JaniceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Foley, A. ReghanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gutowski, NicholasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jungbluth, HeinzUNSPECIFIEDorcid.org/0000-0002-7159-3427UNSPECIFIED
Lassche, SaskiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lavin, TimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marcelis, CarloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marks, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marini-Bettolo, ChiaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Medne, LivijaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moslemi, Ali-RezaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sarkozy, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reilly, Mary M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muntoni, FrancescoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Millan, FranciscaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muraresku, Colleen C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Need, Anna C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nemeth, Andrea H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neuhaus, Sarah B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Norwood, FionaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
O'Donnell, MarieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
O'Driscoll, MaryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rankin, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yum, Sabrina W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zolkipli-Cunningham, ZarazuelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brusius, IsabellUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wunderlich, GilbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karakaya, MertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wirth, BrunhildeUNSPECIFIEDorcid.org/0000-0003-4051-5191UNSPECIFIED
Fakhro, Khalid A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tajsharghi, HomaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bonnemann, Carsten G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Taylor, Jenny C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Houlden, HenryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-607134
DOI: 10.1093/brain/awaa420
Journal or Publication Title: Brain
Volume: 144
Page Range: S. 584 - 601
Date: 2021
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2156
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MATRIX PROTEIN WARP; ZEBRAFISH; MUTATIONS; MODEL; GENOTYPE; SEQUENCE; GENOMEMultiple languages
Clinical Neurology; NeurosciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60713

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