Journal of Neurology

, Volume 266, Issue 2, pp 498–506 | Cite as

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

  • Yanan Sun
  • Hai Chen
  • Yan Lu
  • Jianying Duo
  • Lin Lei
  • Yasheng OuYang
  • Yifeng Hao
  • Yuwei DaEmail author
  • Xin-Ming ShenEmail author
Original Communication


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.


Limb girdle muscular dystrophy LGMD1G LGMD D3 LGMD D3-HNRNPDL related HNRPDL HNRNPDL 



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).

Compliance with ethical standards

Conflicts of interest

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

Ethical standards

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.


  1. 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 28:702–710CrossRefGoogle Scholar
  2. 2.
    Angelini C, Giaretta L, Marozzo R (2018) An update on diagnostic options and considerations in limb-girdle dystrophies. Expert Rev Neurother 18:693–703CrossRefGoogle Scholar
  3. 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 12:1033–1040CrossRefGoogle Scholar
  4. 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 23:4103–4110CrossRefGoogle Scholar
  5. 5.
    Geuens T, Bouhy D, Timmerman V (2016) The hnRNP family: insights into their role in health and disease. Hum Genet 135:851–867CrossRefGoogle Scholar
  6. 6.
    Taylor JP (2015) Multisystem proteinopathy: intersecting genetics in muscle, bone, and brain degeneration. Neurology 85:658–660CrossRefGoogle Scholar
  7. 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 495:467–473CrossRefGoogle Scholar
  8. 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:e25200CrossRefGoogle Scholar
  9. 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 14:102CrossRefGoogle Scholar
  10. 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 1647:9–18CrossRefGoogle Scholar
  11. 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 20:1528–1537CrossRefGoogle Scholar
  12. 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 467:1061–1073CrossRefGoogle Scholar
  13. 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–D845CrossRefGoogle Scholar
  14. 14.
    Bonne G, Rivier F, Hamroun D (2017) The 2018 version of the gene table of monogenic neuromuscular disorders (nuclear genome). Neuromuscul Disord 27:1152–1183CrossRefGoogle Scholar
  15. 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 69:1005–1013CrossRefGoogle Scholar
  16. 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 368:389–391CrossRefGoogle Scholar
  17. 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 7:807–812CrossRefGoogle Scholar
  18. 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 62:390–405CrossRefGoogle Scholar
  19. 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 14:279–293CrossRefGoogle Scholar
  20. 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 128:1164–1177CrossRefGoogle Scholar
  21. 21.
    Meinke P, Nguyen TD, Wehnert MS (2011) The LINC complex and human disease. Biochem Soc Trans 39:1693–1697CrossRefGoogle Scholar
  22. 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. Google Scholar
  23. 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 60:1519–1523CrossRefGoogle Scholar
  24. 24.
    Nonaka I (1994) [Muscle pathologic diagnosis—mechanism in muscle fiber degeneration]. Rinsho Shinkeigaku 34:1279–1281Google Scholar
  25. 25.
    Jongen PJ, Ter Laak HJ, Stadhouders AM (1995) Rimmed basophilic vacuoles and filamentous inclusions in neuromuscular disorders. Neuromuscul Disord 5:31–38CrossRefGoogle Scholar
  26. 26.
    Gilchrist JM, Pericak-Vance M, Silverman L, Roses AD (1988) Clinical and genetic investigation in autosomal dominant limb-girdle muscular dystrophy. Neurology 38:5–9CrossRefGoogle Scholar
  27. 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 81:834–839CrossRefGoogle Scholar
  28. 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 1588:33–40CrossRefGoogle Scholar
  29. 29.
    Hong D, Zhang W, Wang W, Wang Z, Yuan Y (2011) Asian patients with limb girdle muscular dystrophy 2I (LGMD2I). J Clin Neurosci 18:494–499CrossRefGoogle Scholar
  30. 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 33:3866–3874CrossRefGoogle Scholar
  31. 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 277:2732–2739CrossRefGoogle Scholar
  32. 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 12:1139–1151CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Yanan Sun
    • 1
    • 2
  • Hai Chen
    • 1
  • Yan Lu
    • 1
  • Jianying Duo
    • 1
  • Lin Lei
    • 1
  • Yasheng OuYang
    • 1
  • Yifeng Hao
    • 3
  • Yuwei Da
    • 1
    Email author
  • Xin-Ming Shen
    • 4
    Email author
  1. 1.Department of NeurologyXuanwu Hospital, Capital, Medical UniversityBeijingChina
  2. 2.Department of NeurologyDalian Municipal Friendship HospitalDalianChina
  3. 3.Department of RehabilitationDalian hospital of Traditional Chinese MedicineDalianChina
  4. 4.Department of NeurologyMayo ClinicRochesterUSA

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