Advertisement

Human Genetics

, Volume 133, Issue 11, pp 1419–1429 | Cite as

Identification of a homozygous splice site mutation in the dynein axonemal light chain 4 gene on 22q13.1 in a large consanguineous family from Pakistan with congenital mirror movement disorder

  • Iltaf Ahmed
  • Kirti Mittal
  • Taimoor I. Sheikh
  • Nasim Vasli
  • Muhammad Arshad Rafiq
  • Anna Mikhailov
  • Mehrnaz Ohadi
  • Huda Mahmood
  • Guy A. Rouleau
  • Attya Bhatti
  • Muhammad Ayub
  • Myriam Srour
  • Peter John
  • John B. Vincent
Original Investigation

Abstract

Mirror movements (MRMV) are involuntary movements on one side of the body that mirror voluntary movements on the opposite side. Congenital mirror movement disorder is a rare, typically autosomal-dominant disorder, although it has been suspected that some sporadic cases may be due to recessive inheritance. Using a linkage analysis and a candidate gene approach, two genes have been implicated in congenital MRMV disorder to date: DCC on 18q21.2 (MRMV1), which encodes a netrin receptor, and RAD51 on 15q15.1 (MRMV2), which is involved in the maintenance of genomic integrity. Here, we describe a large consanguineous Pakistani family with 11 cases of congenital MRMV disorder reported across five generations, with autosomal recessive inheritance likely. Sanger sequencing of DCC and RAD51 did not identify a mutation. We then employed microarray genotyping and autozygosity mapping to identify a shared region of homozygosity-by-descent among the affected individuals. We identified a large autozygous region of ~3.3 Mb on chromosome 22q13.1 (Chr22:36605976−39904648). We used Sanger sequencing to exclude several candidate genes within this region, including DMC1 and NPTXR. Whole exome sequencing was employed, and identified a splice site mutation in the dynein axonemal light chain 4 gene, DNAL4. This splice site change leads to skipping of exon 3, and omission of 28 amino acids from DNAL4 protein. Linkage analysis using Simwalk2 gives a maximum Lod score of 6.197 at this locus. Whether or how DNAL4 function may relate to the function of DCC or RAD51 is not known. Also, there is no suggestion of primary ciliary dyskinesis, situs inversus, or defective sperm in affected family members, which might be anticipated given a putative role for DNAL4 in axonemal-based dynein complexes. We suggest that DNAL4 plays a role in the cytoplasmic dynein complex for netrin-1-directed retrograde transport, and in commissural neurons of the corpus callosum in particular. This, in turn, could lead to faulty cross-brain wiring, resulting in MRMV.

Keywords

Sanger Sequencing Splice Site Mutation Primary Ciliary Dyskinesis Situs Inversus Unaffected Family Member 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We wish to thank the family members for their willing participation and cooperation with this study. This research was supported by a grant from the Canadian Institutes of Health Research (#MOP-102758), and by the Pakistan Higher Education Commission (HEC). We declare that the authors have no competing interests for this article.

Supplementary material

439_2014_1475_MOESM1_ESM.docx (41 kb)
Supplementary material 1 (DOCX 40 kb)

References

  1. Beaulé V, Tremblay S, Theoret H (2012) Interhemispheric control of unilateral movement. Neural Plast 2012:627816. doi: 10.1155/2012/627816 PubMedPubMedCentralGoogle Scholar
  2. Bonnet C, Roubertie A, Doummar D, Bahi-Buisson N, Cochen de Cock V, Roze E (2010) Developmental and benign movement disorders in childhood. Mov Disord 25:1317–1334. doi: 10.1002/mds.22944 PubMedCrossRefGoogle Scholar
  3. Cincotta M, Borgheresi A, Balzini L, Vannucchi L, Zeloni G, Ragazzoni A, Benvenuti F, Zaccara G, Arnetoli G, Ziemann U (2003) Separate ipsilateral and contralateral corticospinal projections in congenital mirror movements: neurophysiological evidence and significance for motor rehabilitation. Mov Disord 18:1294–1300PubMedCrossRefGoogle Scholar
  4. Cohen LG, Meer J, Tarkka I, Bierner S, Leiderman DB, Dubinsky RM, Sanes JN, Jabbari B, Branscum B, Hallett M (1991) Congenital mirror movements. Abnormal organization of motor pathways in two patients. Brain 114:381–403PubMedCrossRefGoogle Scholar
  5. David M, Dzamba M, Lister D, Ilie L, Brudno M (2011) SHRiMP2: sensitive yet practical short read mapping. Bioinformatics 27:1011–2101. doi: 10.1093/bioinformatics/btr046 PubMedCrossRefGoogle Scholar
  6. Depienne C, Cincotta M, Billot S, Bouteiller D, Groppa S, Brochard V, Flamand C, Hubsch C, Meunier S, Giovannelli F, Klebe S, Corvol JC, Vidailhet M, Brice A, Roze E (2011) A novel DCC mutation and genetic heterogeneity in congenital mirror movements. Neurology 76:260–264. doi: 10.1212/WNL.0b013e318207b1e0 PubMedCrossRefGoogle Scholar
  7. Depienne C, Bouteiller D, Meneret A, Billot S, Groppa S, Klebe S, Charbonnier-Beaupel F, Corvol JC, Saraiva JP, Brueggemann N, Bhatia K, Cincotta M, Brochard V, Flamand-Roze C, Carpentier W, Meunier S, Marie Y, Gaussen M, Stevanin G, Wehrle R, Vidailhet M, Klein C, Dusart I, Brice A, Roze E (2012) RAD51 haploinsufficiency causes congenital mirror movements in humans. Am J Hum Genet 90:301–307. doi: 10.1016/j.ajhg.2011.12.002 PubMedCrossRefPubMedCentralGoogle Scholar
  8. Gallea C, Popa T, Hubsch C, Valabregue R, Brochard V, Kundu P, Schmitt B, Bardinet E, Bertasi E, Flamand-Roze C, Alexandre N, Delmaire C, Méneret A, Depienne C, Poupon C, Hertz-Pannier L, Cincotta M, Vidailhet M, Lehericy S, Meunier S, Roze E (2013) RAD51 deficiency disrupts the corticospinal lateralization of motor control. Brain 136:3333–3346. doi: 10.1093/brain/awt258 PubMedCrossRefGoogle Scholar
  9. Galléa C, Popa T, Billot S, Méneret A, Depienne C, Roze E (2011) Congenital mirror movements: a clue to understanding bimanual motor control. J Neurol 258:1911–1919. doi: 10.1007/s00415-011-6107-9 PubMedCrossRefGoogle Scholar
  10. González-Pérez A, López-Bigas N (2011) Improving the assessment of the outcome of nonsynonymous SNVs with a Consensus Deleteriousness Score, Condel. Am J Hum Genet 88:440–449. doi: 10.1016/j.ajhg.2011.03.004 PubMedCrossRefPubMedCentralGoogle Scholar
  11. Homer N, Nelson SF (2010) Improved variant discovery through local re-alignment of short-read next-generation sequencing data using SRMA. Genome Biol 11:R99. doi: 10.1186/gb-2010-11-10-r99 PubMedCrossRefPubMedCentralGoogle Scholar
  12. Iwasaki M, Kuwata T, Yamazaki Y, Jenkins NA, Copeland NG, Osato M, Ito Y, Kroon E, Sauvageau G, Nakamura T (2005) Identification of cooperative genes for NUP98-HOXA9 in myeloid leukemogenesis using a mouse model. Blood 105:784–793PubMedCrossRefGoogle Scholar
  13. Lahiri DK, Bye S, Nurnberger JI Jr, Hodes ME, Crisp M (1992) A non-organic and non-enzymatic extraction method gives higher yields of genomic DNA from whole-blood samples than do nine other methods tested. J Biochem Biophys Methods 25:193–205PubMedCrossRefGoogle Scholar
  14. Magdaleno S, Jensen P, Brumwell CL, Seal A, Lehman K, Asbury A, Cheung T, Cornelius T, Batten DM, Eden C, Norland SM, Rice DS, Dosooye N, Shakya S, Mehta P, Curran T (2006) BGEM: an in situ hybridization database of gene expression in the embryonic and adult mouse nervous system. PLoS Biol 4:e86PubMedCrossRefPubMedCentralGoogle Scholar
  15. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M, DePristo MA (2010) The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20:1297–1303. doi: 10.1101/gr.107524.110 PubMedCrossRefPubMedCentralGoogle Scholar
  16. Nagao Y, Cheng J, Kamura K, Seki R, Maeda A, Nihei D, Koshida S, Wakamatsu Y, Fujimoto T, Hibi M, Hashimoto H (2010) Dynein axonemal intermediate chain 2 is required for formation of the left–right body axis and kidney in medaka. Dev Biol 347:53–61. doi: 10.1016/j.ydbio.2010.08.001 PubMedCrossRefGoogle Scholar
  17. Omran H, Kobayashi D, Olbrich H, Tsukahara T, Loges NT, Hagiwara H, Zhang Q, Leblond G, O’Toole E, Hara C, Mizuno H, Kawano H, Fliegauf M, Yagi T, Koshida S, Miyawaki A, Zentgraf H, Seithe H, Reinhardt R, Watanabe Y, Kamiya R, Mitchell DR, Takeda H (2008) Ktu/PF13 is required for cytoplasmic pre-assembly of axonemal dyneins. Nature 456:611–616. doi: 10.1038/nature07471 PubMedCrossRefPubMedCentralGoogle Scholar
  18. Pennarun G, Escudier E, Chapelin C, Bridoux A-M, Cacheux V, Roger G, Clement A, Goossens M, Amselem S, Duriez B (1999) Loss-of-function mutations in a human gene related to Chlamydomonas reinhardtii dynein IC78 result in primary ciliary dyskinesia. Am J Hum Genet 65:1508–1519PubMedCrossRefPubMedCentralGoogle Scholar
  19. Phillis R, Statton D, Caruccio P, Murphey RK (1996) Mutations in the 8 kDa dynein light chain gene disrupt sensory axon projections in the Drosophila imaginal CNS. Development 122:2955–2963PubMedGoogle Scholar
  20. Qu C, Dwyer T, Shao Q, Yang T, Huang H, Liu G (2013) Direct binding of TUBB3 with DCC couples netrin-1 signaling to intracellular microtubule dynamics in axon outgrowth and guidance. J Cell Sci 126:3070–3081. doi: 10.1242/jcs.122184 PubMedCrossRefPubMedCentralGoogle Scholar
  21. Rasmussen P (1993) Persistent mirror movement. A clinical study of 17 children, adolescents and young adults. Dev Med Child Neurol 35:699–707PubMedCrossRefGoogle Scholar
  22. Regli F, Filippa G, Wiesendanger M (1967) Hereditary mirror movements. Arch Neurol 16:620–623PubMedCrossRefGoogle Scholar
  23. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (2005) Towards a proteome-scale map of the human protein–protein interaction network. Nature 437:1173–1178PubMedCrossRefGoogle Scholar
  24. Seelow D, Schuelke M, Hildebrandt F, Nürnberg P (2009) HomozygosityMapper—an interactive approach to homozygosity mapping. Nucleic Acids Res 37(Web Server issue):W593–W599. doi: 10.1093/nar/gkp369 PubMedCrossRefPubMedCentralGoogle Scholar
  25. Sobel E, Lange K (1996) Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker sharing statistics. Am J Hum Genet 58:1323–1337PubMedPubMedCentralGoogle Scholar
  26. Sobel E, Sengul H, Weeks DE (2001) Multipoint estimation of identity-by-descent probabilities at arbitrary positions among marker loci on general pedigrees. Hum Hered 52:121–131PubMedCrossRefGoogle Scholar
  27. Sobel E, Papp JC, Lange K (2002) Detection and integration of genotyping errors in statistical genetics. Am J Hum Genet 70:496–508PubMedCrossRefPubMedCentralGoogle Scholar
  28. Srour M, Philibert M, Dion MH, Duquette A, Richer F, Rouleau GA, Chouinard S (2009) Familial congenital mirror movements: report of a large 4-generation family. Neurology 73:729–731. doi: 10.1212/WNL.0b013e3181b59bda PubMedCrossRefPubMedCentralGoogle Scholar
  29. Srour M, Riviére JB, Pham JM, Dubé MP, Girard S, Morin S, Dion PA, Asselin G, Rochefort D, Hince P, Diab S, Sharafaddinzadeh N, Chouinard S, Théoret H, Charron F, Rouleau GA (2010) Mutations in DCC cause congenital mirror movements. Science 328:592. doi: 10.1126/science.1186463 PubMedCrossRefGoogle Scholar
  30. Tanner CA, Rompolas P, Patel-King RS, Gorbatyuk O, Wakabayashi K, Pazour GJ, King SM (2008) Three members of the LC8/DYNLL family are required for outer arm dynein motor function. Mol Biol Cell 19:3724–3734. doi: 10.1091/mbc.E08-04-0362 PubMedCrossRefPubMedCentralGoogle Scholar
  31. Tcherkezian J, Brittis PA, Thomas F, Roux PP, Flanagan JG (2010) Transmembrane receptor DCC associates with protein synthesis machinery and regulates translation. Cell 141:632–644. doi: 10.1016/j.cell.2010.04.008 PubMedCrossRefPubMedCentralGoogle Scholar
  32. Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38:e164. doi: 10.1093/nar/gkq603 PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Iltaf Ahmed
    • 1
    • 2
  • Kirti Mittal
    • 1
  • Taimoor I. Sheikh
    • 1
    • 8
  • Nasim Vasli
    • 1
  • Muhammad Arshad Rafiq
    • 1
  • Anna Mikhailov
    • 1
  • Mehrnaz Ohadi
    • 1
  • Huda Mahmood
    • 1
  • Guy A. Rouleau
    • 3
  • Attya Bhatti
    • 2
  • Muhammad Ayub
    • 4
  • Myriam Srour
    • 5
    • 6
  • Peter John
    • 2
  • John B. Vincent
    • 1
    • 7
    • 8
  1. 1.Molecular Neuropsychiatry and Development (MiND) Lab, Centre For Addiction and Mental HealthCampbell Family Mental Health Research Institute, R32TorontoCanada
  2. 2.Atta-ur-Rehman School of Applied Biosciences (ASAB)National University of Sciences and Technology (NUST)IslamabadPakistan
  3. 3.Montreal Neurological Institute and HospitalMcGill UniversityMontrealCanada
  4. 4.Division of Developmental Disabilities, Department of PsychiatryQueen’s UniversityKingstonCanada
  5. 5.Division of Pediatric Neurology, Departments of Neurology/NeurosurgeryMontreal Children’s Hospital-McGill University Health CentreMontrealCanada
  6. 6.Division of Pediatric Neurology, Department of PediatricsMontreal Children’s Hospital-McGill University Health CentreMontrealCanada
  7. 7.Department of PsychiatryUniversity of TorontoTorontoCanada
  8. 8.Institute of Medical ScienceUniversity of TorontoTorontoCanada

Personalised recommendations