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