Isfahan University of Medical Sciences

Science Communicator Platform

Stay connected! Follow us on X network (Twitter):
Share By
An Ancestral 10-Bp Repeat Expansion in Vwa1 Causes Recessive Hereditary Motor Neuropathy Publisher Pubmed



Pagnamenta AT1 ; Kaiyrzhanov R2 ; Zou Y3 ; Daas SI4 ; Maroofian R2 ; Donkervoort S3 ; Dominik N2 ; Lauffer M5 ; Ferla MP1 ; Orioli A6, 7 ; Giess A6, 7 ; Tucci A6, 7 ; Beetz C8 ; Sedghi M9 Show All Authors
Authors
  1. Pagnamenta AT1
  2. Kaiyrzhanov R2
  3. Zou Y3
  4. Daas SI4
  5. Maroofian R2
  6. Donkervoort S3
  7. Dominik N2
  8. Lauffer M5
  9. Ferla MP1
  10. Orioli A6, 7
  11. Giess A6, 7
  12. Tucci A6, 7
  13. Beetz C8
  14. Sedghi M9
  15. Ansari B10
  16. Barresi R11, 12
  17. Basiri K10
  18. Cortese A2
  19. Elgar G6, 7
  20. Fernandezgarcia MA13
  21. Yip J2
  22. Foley AR3
  23. Gutowski N14
  24. Jungbluth H13, 15, 16
  25. Lassche S17
  26. Lavin T18
  27. Marcelis C19
  28. Marks P20
  29. Marinibettolo C11, 12
  30. Medne L21
  31. Moslemi AR22
  32. Sarkozy A23
  33. Reilly MM2
  34. Muntoni F23
  35. Millan F24
  36. Muraresku CC25
  37. Need AC6, 7
  38. Nemeth AH26, 27
  39. Neuhaus SB3
  40. Norwood F28
  41. Odonnell M20
  42. Odriscoll M20
  43. Rankin J29
  44. Yum SW30
  45. Zolkiplicunningham Z25, 31
  46. Brusius I5
  47. Wunderlich G32
  48. Karakaya M5
  49. Wirth B5
  50. Fakhro KA4, 33, 34
  51. Tajsharghi H35
  52. Bonnemann CG3
  53. Taylor JC1
  54. Houlden H2

Source: Brain Published:2021


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. © 2021 The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.