Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles

Abstract

The muscle specific isoform of the supervillin protein (SV2), encoded by the SVIL gene, is a large sarcolemmal myosin II- and F-actin-binding protein. Supervillin (SV2) binds and co-localizes with costameric dystrophin and binds nebulin, potentially attaching the sarcolemma to myofibrillar Z-lines. Despite its important role in muscle cell physiology suggested by various in vitro studies, there are so far no reports of any human disease caused by SVIL mutations. We here report four patients from two unrelated, consanguineous families with a childhood/adolescence onset of a myopathy associated with homozygous loss-of-function mutations in SVIL. Wide neck, anteverted shoulders and prominent trapezius muscles together with variable contractures were characteristic features. All patients showed increased levels of serum creatine kinase but no or minor muscle weakness. Mild cardiac manifestations were observed. Muscle biopsies showed complete loss of large supervillin isoforms in muscle fibres by western blot and immunohistochemical analyses. Light and electron microscopic investigations revealed a structural myopathy with numerous lobulated muscle fibres and considerable myofibrillar alterations with a coarse and irregular intermyofibrillar network. Autophagic vacuoles, as well as frequent and extensive deposits of lipoproteins, including immature lipofuscin, were observed. Several sarcolemma-associated proteins, including dystrophin and sarcoglycans, were partially mis-localized. The results demonstrate the importance of the supervillin (SV2) protein for the structural integrity of muscle fibres in humans and show that recessive loss-of-function mutations in SVIL cause a distinctive and novel myopathy.

Biallelic loss-of-function variants in WDR11 are associated with microcephaly and intellectual disability

“…Written informed consent was obtained from all participating family members of the three families. Whole-exome sequencing (WES) in family A, individual III-1 and III-2 was performed at the Institute of Human Genetics, RWTH Aachen University, Medical Faculty, as previously described [ 4 ]. GeneMatcher [ 5 ] facilitated identification of two other families (B and C) with homozygous loss-of-function variants in WDR11 .…”

GSK-3β Localizes to the Cardiac Z-Disc to Maintain Length Dependent Activation

“…Mass spectrometry analysis of phospho-enriched myofilament samples from GSK-3β control (n=4) and knockout mice (n=5) identified 981 phospho-sites on 305 proteins (Table S5). Using cutoffs of P <0.05 and log 2 FC<−0.5, we found decreased phosphorylation at 9 S/T residues on 8 proteins in the knockout mice, including the structural z-disc protein abLIM-1, 50 and z-disc affiliated proteins Supervillin, 51 Synaptopodin, 52 and SPEG (striated muscle preferentially expressed protein kinase) (Figure 3A and 3B), suggesting they are GSK-3β targets. Two phosphorylation sites increased (log 2 FC>0.5, HSPB6 (heat shock protein beta-6) and B3AT [band 3 anion transport protein]).…”

Congenital heart defects associated with pathogenic variants in WAC gene: Expanding the phenotypic and genotypic spectrum of DeSanto–Shinawi syndrome

“…Biallelic loss-of-function variants in SVIL have been recently associated with a structural myopathy and mild cardiac involvement (ECG abnormalities and slightly ventricular hypertrophy) (Hedberg-Oldfors et al, 2020). LYZL1 was not associated with human disorders until now.…”