PUBLICATION

An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy

Authors
Pagnamenta, A.T., Kaiyrzhanov, R., Zou, Y., Da'as, S.I., Maroofian, R., Donkervoort, S., Dominik, N., Lauffer, M., Ferla, M.P., Orioli, A., Giess, A., Tucci, A., Beetz, C., Sedghi, M., Ansari, B., Barresi, R., Basiri, K., Cortese, A., Elgar, G., Fernandez-Garcia, M.A., Yip, J., Foley, A.R., Gutowski, N., Jungbluth, H., Lassche, S., Lavin, T., Marcelis, C., Marks, P., Marini-Bettolo, C., Medne, L., Moslemi, A.R., Sarkozy, A., Reilly, M.M., Muntoni, F., Millan, F., Muraresku, C.C., Need, A.C., Nemeth, A.H., Neuhaus, S.B., Norwood, F., O'Donnell, M., O'Driscoll, M., Rankin, J., Yum, S.W., Zolkipli-Cunningham, Z., Brusius, I., Wunderlich, G., Genomics England Research Consortium , Karakaya, M., Wirth, B., Fakhro, K.A., Tajsharghi, H., Bönnemann, C.G., Taylor, J.C., Houlden, H.
ID
ZDB-PUB-210210-6
Date
2021
Source
Brain : a journal of neurology   144(2): 584-600 (Journal)
Registered Authors
Keywords
EMG, genetics: neuropathy, hereditary motor and sensory neuropathies, nerve conduction studies, whole-genome sequencing
MeSH Terms
  • Adult
  • Aged
  • Animals
  • Behavior, Animal/physiology
  • Child
  • Extracellular Matrix Proteins/genetics*
  • Female
  • Hereditary Sensory and Motor Neuropathy/genetics*
  • Hereditary Sensory and Motor Neuropathy/pathology
  • Humans
  • Male
  • Middle Aged
  • Muscle, Skeletal/pathology
  • Mutation
  • Pedigree
  • Young Adult
  • Zebrafish
PubMed
33559681 Full text @ Brain
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 >7000 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.
Genes / Markers
Figures
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes