Abstract
Whole-exome sequencing of two affected sibs and their mother who showed a unique quadriceps-dominant form of neurogenic muscular atrophy disclosed a heterozygous DYNC1H1 mutation [p.H306R (c.917A>G)]. The identical mutation was recently reported in a pedigree with the axonal form of Charcot–Marie–Tooth disease. Three other missense mutations in DYNC1H1 were also identified in families with dominant spinal muscular atrophy with lower extremity predominance. Their clinical features were consistent with those of our family. Our study has demonstrated that the same DYNC1H1 mutation could cause spinal muscular atrophy as well as distal neuropathy, indicating pleotropic effects of the mutation.
This is a preview of subscription content, log in via an institution to check access.
References
Pfister KK, Shah PR, Hummerich H, Russ A, Cotton J, Annuar AA, King SM, Fisher EM (2006) Genetic analysis of the cytoplasmic dynein subunit families. PLoS Genet 2(1):e1. doi:10.1371/journal.pgen.0020001
Weedon MN, Hastings R, Caswell R, Xie W, Paszkiewicz K, Antoniadi T, Williams M, King C, Greenhalgh L, Newbury-Ecob R, Ellard S (2011) Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot–Marie–Tooth disease. Am J Hum Genet 89(2):308–312. doi:10.1016/j.ajhg.2011.07.002
Harms MB, Ori-McKenney KM, Scoto M, Tuck EP, Bell S, Ma D, Masi S, Allred P, Al-Lozi M, Reilly MM, Miller LJ, Jani-Acsadi A, Pestronk A, Shy ME, Muntoni F, Vallee RB, Baloh RH (2012) Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy. Neurology 78(22):1714–1720. doi:10.1212/WNL.0b013e3182556c05
Willemsen MH, Vissers LE, Willemsen MA, van Bon BW, Kroes T, de Ligt J, de Vries BB, Schoots J, Lugtenberg D, Hamel BC, van Bokhoven H, Brunner HG, Veltman JA, Kleefstra T (2012) Mutations in DYNC1H1 cause severe intellectual disability with neuronal migration defects. J Med Genet 49(3):179–183. doi:10.1136/jmedgenet-2011-100542
Tsurusaki Y, Okamoto N, Suzuki Y, Doi H, Saitsu H, Miyake N, Matsumoto N (2011) Exome sequencing of two patients in a family with atypical X-linked leukodystrophy. Clin Genet 80(2):161–166. doi:10.1111/j.1399-0004.2011.01721.x
Saitsu H, Osaka H, Sasaki M, Takanashi J, Hamada K, Yamashita A, Shibayama H, Shiina M, Kondo Y, Nishiyama K, Tsurusaki Y, Miyake N, Doi H, Ogata K, Inoue K, Matsumoto N (2011) Mutations in POLR3A and POLR3B encoding RNA polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy. Am J Hum Genet 89(5):644–651. doi:10.1016/j.ajhg.2011.10.003
Doi H, Yoshida K, Yasuda T, Fukuda M, Fukuda Y, Morita H, Ikeda S, Kato R, Tsurusaki Y, Miyake N, Saitsu H, Sakai H, Miyatake S, Shiina M, Nukina N, Koyano S, Tsuji S, Kuroiwa Y, Matsumoto N (2011) Exome sequencing reveals a homozygous SYT14 mutation in adult-onset, autosomal-recessive spinocerebellar ataxia with psychomotor retardation. Am J Hum Genet 89(2):320–327. doi:10.1016/j.ajhg.2011.07.012
Hafezparast M, Klocke R, Ruhrberg C, Marquardt A, Ahmad-Annuar A, Bowen S, Lalli G, Witherden AS, Hummerich H, Nicholson S, Morgan PJ, Oozageer R, Priestley JV, Averill S, King VR, Ball S, Peters J, Toda T, Yamamoto A, Hiraoka Y, Augustin M, Korthaus D, Wattler S, Wabnitz P, Dickneite C, Lampel S, Boehme F, Peraus G, Popp A, Rudelius M, Schlegel J, Fuchs H, Hrabe de Angelis M, Schiavo G, Shima DT, Russ AP, Stumm G, Martin JE, Fisher EM (2003) Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science 300(5620):808–812. doi:10.1126/science.1083129
Chen XJ, Levedakou EN, Millen KJ, Wollmann RL, Soliven B, Popko B (2007) Proprioceptive sensory neuropathy in mice with a mutation in the cytoplasmic dynein heavy chain 1 gene. J Neurosci 27(52):14515–14524. doi:10.1523/JNEUROSCI.4338-07.2007
Ori-McKenney KM, Vallee RB (2011) Neuronal migration defects in the Loa dynein mutant mouse. Neural Dev 6:26. doi:10.1186/1749-8104-6-26
Acknowledgments
We would like to thank the family for their participation in this study. This work was supported by research grants from the Ministry of Health, Labour and Welfare (H.S., N. Miyake, and N. Matsumoto); a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (N. Miyake and N. Matsumoto); a grant from the Japan Science and Technology Agency (N. Matsumoto), the Strategic Research Program for Brain Sciences (N. Matsumoto); a Grant-in-Aid for Scientific Research on Innovative Areas (Foundation of Synapse and Neurocircuit Pathology) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (N. Matsumoto); a research grant from Naito Foundation (N. Matsumoto); and research grants from Takeda Science Foundation (N. Miyake and N. Matsumoto). This work was performed at the Advanced Medical Research Center, Yokohama City University, Japan.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Authorship
Y.T. and S.S. contributed equally to this work.
Rights and permissions
About this article
Cite this article
Tsurusaki, Y., Saitoh, S., Tomizawa, K. et al. A DYNC1H1 mutation causes a dominant spinal muscular atrophy with lower extremity predominance. Neurogenetics 13, 327–332 (2012). https://doi.org/10.1007/s10048-012-0337-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10048-012-0337-6