Milder forms of muscular dystrophy associated with POMGNT2 mutations

Abstract

Objective:To determine the genetic variants in patients with dystroglycanopathy (DGP) and assess the pathogenicity of these variants.Methods:A total of 20 patients with DGP were identified by immunohistochemistry or Western blot analysis. Whole-exome sequencing (WES) was performed using patient samples. The pathogenicity of the variants identified was evaluated on the basis of the phenotypic recovery in a knockout (KO) haploid human cell line by transfection with mutated POMGNT2 cDNA and on the basis of the in vitro enzymatic activity of mutated proteins.Results:WES identified homozygous and compound heterozygous missense variants in POMGNT2 in 3 patients with the milder limb-girdle muscular dystrophy (LGMD) and intellectual disability without brain malformation. The 2 identified variants were located in the putative glycosyltransferase domain of POMGNT2, which affected its enzymatic activity. Mutated POMGNT2 cDNAs failed to rescue the phenotype of POMGNT2-KO cells.Conclusions:Novel variants in POMGNT2 are associated with milder forms of LGMD. The findings of this study expand the clinical and pathologic spectrum of DGP associated with POMGNT2 variants from the severest Walker-Warburg syndrome to the mildest LGMD phenotypes. The simple method to verify pathogenesis of variants may allow researchers to evaluate any variants present in all of the known causative genes and the variants in novel candidate genes to detect DGPs, particularly without using patients' specimens.

Untangling the complexity of limb‐girdle muscular dystrophies

“…First, we exhausted the alphabet for LGMD2 after the recent discovery of LGMD2Z . Second, as indicated earlier, other genetically characterized, autosomally inherited muscle diseases are clinically indistinguishable from LGMD but not categorized as LGMD . Third, mutations in certain LGMD‐related genes give rise to both LGMD1 and LGMD2.…”

“…They share a broad spectrum of muscle, eye, and brain disorders that vary from a severe muscle–eye–brain disease or Walker–Warburg syndrome, to a moderate congenital muscular dystrophy with neuronal migration defects, to a mild LGMD2 with or without intellectual disability and subtle brain anomalies. An LGMD phenotype was recently reported in association with POMGNT2, POMK , and DPM3 mutations, but not yet classified as LGMD2 subtype . Mutations in a few other genes ( B3GALNT2, B4GAT1, DPM2 , and TMEM5 ) were reported to cause a moderate to severe α‐dystroglycanopathy, but an LGMD phenotype has not yet been described .…”

“…17 Second, as indicated earlier, other genetically characterized, autosomally inherited muscle diseases are clinically indistinguishable from LGMD but not categorized as LGMD. [18][19][20][21][22][23][24][25][26] Third, mutations in certain LGMD-related genes give rise to both LGMD1 and LGMD2. For example, dominant mutations in CAV3, DES, and MYOT were first reported to cause LGMD1; however, subsequently, patients with rare recessive mutations in these genes were described, [27][28][29][30][31][32] although only recessive DES myopathy was classified as LGMD2.…”

“…LGMD phenotype was recently reported in association with POMGNT2, POMK, and DPM3 mutations, but not yet classified as LGMD2 subtype. [24][25][26] Mutations in a few other genes (B3GALNT2, B4GAT1, DPM2, and TMEM5) were reported to cause a moderate to severe a-dystroglycanopathy, but an LGMD phenotype has not yet been described. [42][43][44][45][46][47][48] Figure 4 shows the spectrum of a-dystroglycanopathy phenotypes and reported causative genes.…”

Next-generation sequencing in neuromuscular diseases

“…The advent of NGS has in the last decade led to an era of inexpensive, high-throughput DNA sequencing of large numbers of genes in a single reaction, thus facilitating the discovery of novel disease genes and variants (6, 10, 33–35). …”