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Limb girdle muscular dystrophy D3 HNRNPDL related in a Chinese family with distal muscle weakness caused by a mutation in the prion-like domain

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Abstract

Limb-girdle muscular dystrophies (LGMD) are a group of clinically and genetically heterogeneous diseases characterized by weakness and wasting of the pelvic and shoulder girdle muscles. Twenty-four recessive LGMD (types R1–R24) and five dominant LGMD (types D1-D5) have been identified with characterization of mutations in various genes. To date, LGMD D3 (previously known as LGMD1G) has been characterized in only two families with Brazilian or Uruguayan origin. Each was caused by a distinct mutation at codon 378 in the prion-like domain of HNRNPDL encoding heterogeneous nuclear ribonucleoprotein D like (HNRNPDL), an RNA processing protein. Our study characterized eight patients suffering from LGMD D3 in a Chinese family spanning three generations. Muscle biopsy specimens from two patients showed a myopathy with rimmed vacuoles. Sequencing analysis revealed a heterozygous c.1132G > A (p.D378N) mutation in HNRNPDL that co-segregated with disease phenotype in the family. The same mutation has been identified previously in the Brazilian family with LGMD D3. However, most patients in the current family showed distal as well as proximal limb weakness rather than weakness of toe and finger flexor muscles that were typical features in the other two LGMD D3 families reported previously. The present study indicates that the same mutation in HNRNPDL results in various phenotypes of LGMD D3. That all mutations in three unrelated families with different ethnic background occur at the same position in codon 378 of HNRNPDL gene suggests a mutation hotspot. Acceleration of intrinsic self-aggregation of HNRNPDL caused by mutation of the prior-like domain may contribute to the pathogenesis of the disease.

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References

  1. Straub V, Murphy A, Udd B (2018) 229th ENMC international workshop: Limb girdle muscular dystrophies—nomenclature and reformed classification Naarden, the Netherlands, 17–19 March 2017. Neuromuscul Disord 28:702–710

    Article  PubMed  Google Scholar 

  2. Angelini C, Giaretta L, Marozzo R (2018) An update on diagnostic options and considerations in limb-girdle dystrophies. Expert Rev Neurother 18:693–703

    Article  CAS  PubMed  Google Scholar 

  3. Starling A, Kok F, Passos-Bueno MR, Vainzof M, Zatz M (2004) A new form of autosomal dominant limb-girdle muscular dystrophy (LGMD1G) with progressive fingers and toes flexion limitation maps to chromosome 4p21. Eur J Hum Genet 12:1033–1040

    Article  CAS  PubMed  Google Scholar 

  4. Vieira NM, Naslavsky MS, Licinio L, Kok F, Schlesinger D, Vainzof M, Sanchez N, Kitajima JP, Gal L, Cavacana N, Serafini PR, Chuartzman S, Vasquez C, Mimbacas A, Nigro V, Pavanello RC, Schuldiner M, Kunkel LM, Zatz M (2014) A defect in the RNA-processing protein HNRPDL causes limb-girdle muscular dystrophy 1G (LGMD1G). Hum Mol Genet 23:4103–4110

    Article  CAS  PubMed  Google Scholar 

  5. Geuens T, Bouhy D, Timmerman V (2016) The hnRNP family: insights into their role in health and disease. Hum Genet 135:851–867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Taylor JP (2015) Multisystem proteinopathy: intersecting genetics in muscle, bone, and brain degeneration. Neurology 85:658–660

    Article  PubMed  Google Scholar 

  7. Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A, Kanagaraj AP, Carter R, Boylan KB, Wojtas AM, Rademakers R, Pinkus JL, Greenberg SA, Trojanowski JQ, Traynor BJ, Smith BN, Topp S, Gkazi AS, Miller J, Shaw CE, Kottlors M, Kirschner J, Pestronk A, Li YR, Ford AF, Gitler AD, Benatar M, King OD, Kimonis VE, Ross ED, Weihl CC, Shorter J, Taylor JP (2013) Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495:467–473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shorter J, Taylor JP (2013) Disease mutations in the prion-like domains of hnRNPA1 and hnRNPA2/B1 introduce potent steric zippers that drive excess RNP granule assembly. Rare Dis 1:e25200

    Article  PubMed  PubMed Central  Google Scholar 

  9. Navarro S, Marinelli P, Diaz-Caballero M, Ventura S (2015) The prion-like RNA-processing protein HNRPDL forms inherently toxic amyloid-like inclusion bodies in bacteria. Microb Cell Fact 14:102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. March ZM, King OD, Shorter J (2016) Prion-like domains as epigenetic regulators, scaffolds for subcellular organization, and drivers of neurodegenerative disease. Brain Res 1647:9–18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Karaca E, Posey JE, Coban AZ, Pehlivan D, Harel T, Jhangiani SN, Bayram Y, Song X, Bahrambeigi V, Yuregir OO, Bozdogan S, Yesil G, Isikay S, Muzny D, Gibbs RA, Lupski JR (2018) Phenotypic expansion illuminates multilocus pathogenic variation. Genet Med 20:1528–1537

    Article  PubMed  PubMed Central  Google Scholar 

  12. Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA, Hurles ME, McVean GA (2010) A map of human genome variation from population-scale sequencing. Nature 467:1061–1073

    Article  CAS  PubMed  Google Scholar 

  13. Karczewski KJ, Weisburd B, Thomas B, Solomonson M, Ruderfer DM, Kavanagh D, Hamamsy T, Lek M, Samocha KE, Cummings BB, Birnbaum D, Daly MJ, MacArthur DG (2017) The ExAC browser: displaying reference data information from over 60 000 exomes. Nucleic Acids Res 45:D840–D845

    Article  CAS  PubMed  Google Scholar 

  14. Bonne G, Rivier F, Hamroun D (2017) The 2018 version of the gene table of monogenic neuromuscular disorders (nuclear genome). Neuromuscul Disord 27:1152–1183

    Article  PubMed  Google Scholar 

  15. Liang WC, Mitsuhashi H, Keduka E, Nonaka I, Noguchi S, Nishino I, Hayashi YK (2011) TMEM43 mutations in Emery–Dreifuss muscular dystrophy-related myopathy. Ann Neurol 69:1005–1013

    Article  CAS  PubMed  Google Scholar 

  16. Yang X, An R, Zhao Q, Zheng J, Tian S, Chen Y, Xu Y (2016) Mutational analysis of CHCHD2 in Chinese patients with multiple system atrophy and amyotrophic lateral sclerosis. J Neurol Sci 368:389–391

    Article  CAS  PubMed  Google Scholar 

  17. Pan TC, Zhang RZ, Pericak-Vance MA, Tandan R, Fries T, Stajich JM, Viles K, Vance JM, Chu ML, Speer MC (1998) Missense mutation in a von Willebrand factor type A domain of the alpha 3(VI) collagen gene (COL6A3) in a family with Bethlem myopathy. Hum Mol Genet 7:807–812

    Article  CAS  PubMed  Google Scholar 

  18. Baker NL, Morgelin M, Pace RA, Peat RA, Adams NE, Gardner RJ, Rowland LP, Miller G, De Jonghe P, Ceulemans B, Hannibal MC, Edwards M, Thompson EM, Jacobson R, Quinlivan RC, Aftimos S, Kornberg AJ, North KN, Bateman JF, Lamande SR (2007) Molecular consequences of dominant Bethlem myopathy collagen VI mutations. Ann Neurol 62:390–405

    Article  CAS  PubMed  Google Scholar 

  19. Baker NL, Morgelin M, Peat R, Goemans N, North KN, Bateman JF, Lamande SR (2005) Dominant collagen VI mutations are a common cause of Ullrich congenital muscular dystrophy. Hum Mol Genet 14:279–293

    Article  CAS  PubMed  Google Scholar 

  20. Lee Y, Jonson PH, Sarparanta J, Palmio J, Sarkar M, Vihola A, Evila A, Suominen T, Penttila S, Savarese M, Johari M, Minot MC, Hilton-Jones D, Maddison P, Chinnery P, Reimann J, Kornblum C, Kraya T, Zierz S, Sue C, Goebel H, Azfer A, Ralston SH, Hackman P, Bucelli RC, Taylor JP, Weihl CC, Udd B (2018) TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations. J Clin Invest 128:1164–1177

    Article  PubMed  PubMed Central  Google Scholar 

  21. Meinke P, Nguyen TD, Wehnert MS (2011) The LINC complex and human disease. Biochem Soc Trans 39:1693–1697

    Article  CAS  PubMed  Google Scholar 

  22. Mukai T, Mori-Yoshimura M, Nishikawa A, Hokkoku K, Sonoo M, Nishino I, Takahashi Y (2018) Emery-Dreifuss muscular dystrophy-related myopathy with TMEM43 mutations. Muscle Nerve. https://doi.org/10.1002/mus.26355

    Article  PubMed  Google Scholar 

  23. Argov Z, Eisenberg I, Grabov-Nardini G, Sadeh M, Wirguin I, Soffer D, Mitrani-Rosenbaum S (2003) Hereditary inclusion body myopathy: the Middle Eastern genetic cluster. Neurology 60:1519–1523

    Article  CAS  PubMed  Google Scholar 

  24. Nonaka I (1994) [Muscle pathologic diagnosis—mechanism in muscle fiber degeneration]. Rinsho Shinkeigaku 34:1279–1281

    CAS  PubMed  Google Scholar 

  25. Jongen PJ, Ter Laak HJ, Stadhouders AM (1995) Rimmed basophilic vacuoles and filamentous inclusions in neuromuscular disorders. Neuromuscul Disord 5:31–38

    Article  CAS  PubMed  Google Scholar 

  26. Gilchrist JM, Pericak-Vance M, Silverman L, Roses AD (1988) Clinical and genetic investigation in autosomal dominant limb-girdle muscular dystrophy. Neurology 38:5–9

    Article  CAS  PubMed  Google Scholar 

  27. Sandell S, Huovinen S, Sarparanta J, Luque H, Raheem O, Haapasalo H, Hackman P, Udd B (2010) The enigma of 7q36 linked autosomal dominant limb girdle muscular dystrophy. J Neurol Neurosurg Psychiatry 81:834–839

    Article  PubMed  Google Scholar 

  28. Vainzof M, Moreira ES, Suzuki OT, Faulkner G, Valle G, Beggs AH, Carpen O, Ribeiro AF, Zanoteli E, Gurgel-Gianneti J, Tsanaclis AM, Silva HC, Passos-Bueno MR, Zatz M (2002) Telethonin protein expression in neuromuscular disorders. Biochim Biophys Acta 1588:33–40

    Article  CAS  PubMed  Google Scholar 

  29. Hong D, Zhang W, Wang W, Wang Z, Yuan Y (2011) Asian patients with limb girdle muscular dystrophy 2I (LGMD2I). J Clin Neurosci 18:494–499

    Article  PubMed  Google Scholar 

  30. Kim DH, Langlois MA, Lee KB, Riggs AD, Puymirat J, Rossi JJ (2005) HnRNP H inhibits nuclear export of mRNA containing expanded CUG repeats and a distal branch point sequence. Nucleic Acids Res 33:3866–3874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kawamura H, Tomozoe Y, Akagi T, Kamei D, Ochiai M, Yamada M (2002) Identification of the nucleocytoplasmic shuttling sequence of heterogeneous nuclear ribonucleoprotein D-like protein JKTBP and its interaction with mRNA. J Biol Chem 277:2732–2739

    Article  CAS  PubMed  Google Scholar 

  32. Gautrey H, Jackson C, Dittrich AL, Browell D, Lennard T, Tyson-Capper A (2015) SRSF3 and hnRNP H1 regulate a splicing hotspot of HER2 in breast cancer cells. RNA Biol 12:1139–1151

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful to all the subjects for participation in our study. This study was supported by National Key R&D Program of China, Precision Medicine Program–Cohort Study on Nervous System Diseases (No. 2017YFC0907700).

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Authors and Affiliations

  1. Department of Neurology, Xuanwu Hospital, Capital, Medical University, Chang Chun Street, Beijing, 100053, China

    Yanan Sun, Hai Chen, Yan Lu, Jianying Duo, Lin Lei, Yasheng OuYang & Yuwei Da

  2. Department of Neurology, Dalian Municipal Friendship Hospital, Dalian, 116100, Liao Ning, China

    Yanan Sun

  3. Department of Rehabilitation, Dalian hospital of Traditional Chinese Medicine, Dalian, 116013, Liao Ning, China

    Yifeng Hao

  4. Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA

    Xin-Ming Shen

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  1. Yanan Sun
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Correspondence to Yuwei Da or Xin-Ming Shen.

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All authors have reviewed the manuscript. Authors have no conflict of interest to declare.

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The study was conducted after receiving written informed consent from patients. In addition, this study was approved by the Institutional Ethics Committee of Xuanwu Hospital, Capital Medical University, Beijing, China.

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Sun, Y., Chen, H., Lu, Y. et al. Limb girdle muscular dystrophy D3 HNRNPDL related in a Chinese family with distal muscle weakness caused by a mutation in the prion-like domain. J Neurol 266, 498–506 (2019). https://doi.org/10.1007/s00415-018-9165-4

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