A novel mutation in SEPN1 causing rigid spine muscular dystrophy 1: a Case report

Abstract

Background: Muscular dystrophies are a clinically and genetically heterogeneous group of disorders characterized by variable degrees of progressive muscle degeneration and weakness. There is a wide variability in the age of onset, symptoms and rate of progression in subtypes of these disorders. Herein, we present the results of our study conducted to identify the pathogenic genetic variation involved in our patient affected by rigid spine muscular dystrophy.

Case presentation: A 14-year-old boy, product of a first-cousin marriage, was enrolled in our study with failure to thrive, fatigue, muscular dystrophy, generalized muscular atrophy, kyphoscoliosis, and flexion contracture of the knees and elbows. Whole-exome sequencing (WES) was carried out on the DNA of the patient to investigate all coding regions and uncovered a novel, homozygous missense mutation in SEPN1 gene (c. 1379 C > T, p.Ser460Phe). This mutation has not been reported before in different public variant databases and also our database (BayanGene), so it is classified as a variation of unknown significance (VUS). Subsequently, it was confirmed that the novel variation was homozygous in our patient and heterozygous in his parents. Different bioinformatics tools showed the damaging effects of the variant on protein. Multiple sequence alignment using BLASTP on ExPASy and WebLogo, revealed the conservation of the mutated residue.

Conclusion: We reported a novel homozygous mutation in SEPN1 gene that expands our understanding of rigid spine muscular dystrophy. Although bioinformatics analyses of results were in favor of the pathogenicity of the mutation, functional studies are needed to establish the pathogenicity of the variant.

Keywords: Muscular dystrophies; Novel mutation; Rigid spine muscular dystrophy; SEPN1; Selenoproteins.

Fig. 1

Generalized muscular atrophy, kyphoscoliosis, and flexion contracture of the knees and elbows in our patient

Fig. 2

Pedigree and Sanger sequencing chromatogram of family involved in this study

Fig. 3

a: Graphical representation of amino acid multiple sequence alignment among different species. It shows degree of conservation for amino acids 447–465 of SEPN1 protein. Position 460 (serine) indicates the mutated residue in our study. It has middle conservation degree (2 bits) and also shows that it is replaced by two other amino acids, i.e., glycine and proline in other species but not by phenylalanine. A logo represents the height of each letter proportional to the observed frequency of the corresponding amino acid. The overall height of each stack is proportional to the sequence conservation, measured in bits, at that position. The maximum sequence conservation per site is log₂ 20 ≈ 4.32 bits for proteins. The protein sequence alignment was performed for the following species: Homo sapiens (Q9NZV5), Gorilla gorilla gorilla (G3R759), Pongo abelii (H2N8I1), Papio anubis (A0A2I3MR13), Rhinopithecus roxellan (A0A2K6RVS9), Sus scrofa (A1E950), Bos taurus (F1MD36), Myotis lucifugus (G1P3X6), Dipodomys ordii (A0A1S3GIF9), Equus caballus (F7BM99), Loxodonta africana (G5E785), and Mus musculus (D3Z2R5). b: Multiple protein sequence alignment of SEPN1 across different kingdoms