Mutations of the Selenoprotein N Gene, Which Is Implicated in Rigid Spine Muscular Dystrophy, Cause the Classical Phenotype of Multiminicore Disease: Reassessing the Nosology of Early-Onset Myopathies

Abstract

Multiminicore disease (MmD) is an autosomal recessive congenital myopathy characterized by the presence of multiple, short core lesions (known as "minicores") in most muscle fibers. MmD is a clinically heterogeneous condition, in which four subgroups have been distinguished. Homozygous RYR1 mutations have been recently identified in the moderate form of MmD with hand involvement. The genes responsible for the three other forms (including the most prevalent phenotype, termed the "classical" phenotype) remained, so far, unknown. To further characterize the genetic basis of MmD, we analyzed a series of 62 patients through a combined positional/candidate-gene approach. On the basis of clinical and morphological data, we suspected a relationship between classical MmD and the selenoprotein N gene (SEPN1), which is located on chromosome 1p36 (RSMD1 locus) and is responsible for the congenital muscular dystrophy with rigid spine syndrome (RSMD). A genomewide screening, followed by the analysis of 1p36 microsatellite markers in 27 informative families with MmD, demonstrated linkage to RSMD1 in eight families. All showed an axial myopathy with scoliosis and respiratory failure, consistent with the most severe end of the classical MmD spectrum; spinal rigidity was evident in some, but not all, patients. We excluded linkage to RSMD1 in 19 families with MmD, including 9 with classical MmD. Screening of SEPN1 in the 8 families that showed linkage and in 14 patients with classical sporadic disease disclosed 9 mutations affecting 17 patients (12 families); 6 were novel mutations, and 3 had been described in patients with RSMD. Analysis of three deltoid biopsy specimens from patients with typical RSMD revealed a wide myopathological variability, ranging from a dystrophic to a congenital myopathy pattern. A variable proportion of minicores was found in all the samples. The present study represents the first identification of a gene responsible for classical MmD, demonstrates its genetic heterogeneity, and reassesses the nosological boundaries between MmD and RSMD.

Selective up-regulation of human selenoproteins in response to oxidative stress

“…With animal models, it appeared that, although many different phenotypes were characterized, selenoproteins operate at many levels to protect the cells against oxidative stress and maintain redox homeostasis (43,44). Concerning human inherited diseases, only mutations in SBP2 and SelN have been characterized to date (45)(46)(47)(48). Mutations in the recoding factor SBP2 gene that caused a defect in almost all selenoprotein expression led to a severe and complex phenotype, including increased cellular ROS and susceptibility to ultraviolet radiation-induced oxidative damage in skin (46).…”

The Genetics of Malignant Hyperthermia

“…In common with CCD, the cores in MmD lack mitochondria, but they differ in that they do not extend the length of the muscle fiber [44]. Mutations in selenoprotein N (SEPN1) have been the most frequent finding in MmD [51], but other cases of MmD have been found to have variants in the RYR1 [52]. CCD may initially present as MmD.…”

Multi-minicore disease revisited

“…Recently, studies provided evidence for genetic heterogeneity of MmD [8][9][10][11] . Mutation in the skeletal muscle ryanodine receptor (RYR-1) gene (locus 19q13) 8,9,11 , well recognized in CCD, has been found in cases of MmD, thus linking the two diseases at least at the genetic level.…”

“…Mutation in the skeletal muscle ryanodine receptor (RYR-1) gene (locus 19q13) 8,9,11 , well recognized in CCD, has been found in cases of MmD, thus linking the two diseases at least at the genetic level. On the other hand, classical cases of MmD harbor a mutation in the selenoprotein N (SE-PN-1) gene (locus 1p36) 10 , which may also be found in congenital muscular dystrophy with rigid spine syndrome.…”