Muscle and bone characteristics of a Chinese family with spinal muscular atrophy, lower extremity predominant 1 (SMALED1) caused by a novel missense DYNC1H1 mutation.

Publisher: BioMed Central Country of Publication: England NLM ID: 101319628 Publication Model: Electronic Cited Medium: Internet ISSN: 1755-8794 (Electronic) Linking ISSN: 17558794 NLM ISO Abbreviation: BMC Med Genomics Subsets: MEDLINE

Original Publication: London : BioMed Central

Cytoplasmic Dyneins*/genetics ; Muscular Atrophy, Spinal*/genetics; Humans ; Amino Acids ; Atrophy ; East Asian People ; Lower Extremity ; Muscles ; Mutation, Missense

Background: Spinal muscular atrophy, lower extremity predominant (SMALED) is a type of non-5q spinal muscular atrophy characterised by weakness and atrophy of lower limb muscles without sensory abnormalities. SMALED1 can be caused by dynein cytoplasmic 1 heavy chain 1 (DYNC1H1) gene variants. However, the phenotype and genotype of SMALED1 may overlap with those of other neuromuscular diseases, making it difficult to diagnose clinically. Additionally, bone metabolism and bone mineral density (BMD) in patients with SMALED1 have never been reported.
Methods: We investigated a Chinese family in which 5 individuals from 3 generations had lower limb muscle atrophy and foot deformities. Clinical manifestations and biochemical and radiographic indices were analysed, and mutational analysis was performed by whole-exome sequencing (WES) and Sanger sequencing.
Results: A novel mutation in exon 4 of the DYNC1H1 gene (c.587T > C, p.Leu196Ser) was identified in the proband and his affected mother by WES. Sanger sequencing confirmed that the proband and 3 affected family members were carriers of this mutation. As leucine is a hydrophobic amino acid and serine is hydrophilic, the hydrophobic interaction resulting from mutation of amino acid residue 196 could influence the stability of the DYNC1H1 protein. Leg muscle magnetic resonance imaging of the proband revealed severe atrophy and fatty infiltration, and electromyographic recordings showed chronic neurogenic impairment of the lower extremities. Bone metabolism markers and BMD of the proband were all within normal ranges. None of the 4 patients had experienced fragility fractures.
Conclusion: This study identified a novel DYNC1H1 mutation and expands the spectrum of phenotypes and genotypes of DYNC1H1-related disorders. This is the first report of bone metabolism and BMD in patients with SMALED1.
(© 2023. The Author(s).)

Eur J Neurol. 2021 Apr;28(4):1334-1343. (PMID: 33369814)
Curr Mol Med. 2011 Nov;11(8):650-65. (PMID: 21902652)
J Neurosci. 2007 Dec 26;27(52):14515-24. (PMID: 18160659)
Science. 2014 Jul 18;345(6194):337-41. (PMID: 25035494)
J Clin Endocrinol Metab. 2007 Feb;92(2):443-9. (PMID: 17105843)
Cell. 2017 Jun 15;169(7):1303-1314.e18. (PMID: 28602352)
J Hum Genet. 2020 Nov;65(11):1003-1017. (PMID: 32788638)
Autoimmun Rev. 2015 Mar;14(3):204-9. (PMID: 25447288)
Am J Med Genet A. 2020 Sep;182(9):2049-2057. (PMID: 32656949)
Neurology. 2010 Aug 10;75(6):539-46. (PMID: 20697106)
Genes (Basel). 2021 Dec 29;13(1):. (PMID: 35052424)
Zhonghua Er Ke Za Zhi. 2009 Jul;47(7):487-92. (PMID: 19951507)
J Cell Biol. 2005 May 23;169(4):561-7. (PMID: 15911875)
Nat Commun. 2014 Mar 11;5:3411. (PMID: 24614806)
Neurology. 2012 May 29;78(22):1714-20. (PMID: 22459677)
Science. 2015 Mar 27;347(6229):1441-1446. (PMID: 25814576)
Science. 2003 May 2;300(5620):808-12. (PMID: 12730604)
Neuromuscul Disord. 2018 Sep;28(9):750-756. (PMID: 30122514)
Genome Res. 2010 Sep;20(9):1297-303. (PMID: 20644199)
Neuromuscul Disord. 2017 Apr;27(4):331-337. (PMID: 28258940)
Nat Struct Mol Biol. 2011 Jun;18(6):638-42. (PMID: 21602819)
Trends Cell Biol. 2016 May;26(5):327-340. (PMID: 26822037)
Genet Med. 2015 May;17(5):405-24. (PMID: 25741868)
Neuron. 2010 Nov 18;68(4):610-38. (PMID: 21092854)
J Biol Chem. 2010 Jun 11;285(24):18627-39. (PMID: 20382740)
Bone. 2011 Apr 1;48(4):810-9. (PMID: 21182992)
BMC Musculoskelet Disord. 2021 Aug 24;22(1):729. (PMID: 34429096)
J Neurol Neurosurg Psychiatry. 2012 Jan;83(1):6-14. (PMID: 22028385)
Neuromuscul Disord. 2019 Jul;29(7):525-532. (PMID: 31266719)
Mol Neurodegener. 2019 Jul 10;14(1):27. (PMID: 31291987)
Adv Protein Chem. 1988;39:191-234. (PMID: 3072868)
Brain. 2015 Feb;138(Pt 2):293-310. (PMID: 25497877)
Neurogenetics. 2012 Aug;13(3):195-203. (PMID: 22526352)
Bone. 2021 May;146:115879. (PMID: 33561588)
J Biol Chem. 2013 Jan 25;288(4):2271-80. (PMID: 23212922)
Annu Rev Cell Dev Biol. 2015;31:83-108. (PMID: 26436706)
Proc Natl Acad Sci U S A. 2017 Feb 28;114(9):E1597-E1606. (PMID: 28196890)
Bone. 2015 Oct;79:116-20. (PMID: 26055105)
Cold Spring Harb Mol Case Stud. 2022 Mar 24;8(2):. (PMID: 34535505)
Neurochem Res. 2013 Sep 28;:. (PMID: 24078265)

81870618 National Natural Science Foundation of China

Keywords: Bone metabolism; DYNC1H1; SMALED1; Sanger sequencing; Whole-exome sequencing

0 (Amino Acids)
EC 3.6.4.2 (Cytoplasmic Dyneins)
0 (DYNC1H1 protein, human)

Date Created: 20230307 Date Completed: 20230309 Latest Revision: 20230314

20230314

PMC9990223

10.1186/s12920-023-01472-4

36882741