A recessive mutation in beta-IV-spectrin (SPTBN4) associates with congenital myopathy, neuropathy, and central deafness

Abstract

Congenital myopathies are a heterogeneous group of muscle disorders that are often genetically determined. Here, we investigated a boy with congenital myopathy, deafness, and neuropathy from a consanguineous Kurdish family by autozygosity mapping and whole exome sequencing. We found a homozygous nonsense mutation in SPTBN4 [c.1597C>T, NM_020971.2; p.(Q533*), NP_066022.2; ClinVar SUB2292235] encoding βIV-spectrin, a non-erythrocytic member of the β-spectrin family. Western blot confirmed the absence of the full-length 288 kDa isoform in muscle and of a specific 72 kDa isoform in fibroblasts. Clinical symptoms of the patient largely corresponded to those described for the quivering mouse, a loss-of-function animal model. Since the human phenotype of βIV-spectrin deficiency included a myopathy with incomplete congenital fiber-type disproportion, we investigated muscle of the quivering (qv4J) mouse and found complete absence of type 1 fibers (fiber-type 2 uniformity). Immunohistology confirmed expression of βIV-spectrin in normal human and mouse muscle at the sarcolemma and its absence in patient and quivering (qv4J) mouse. SPTBN4 mRNA-expression levels in healthy skeletal muscle were found in the range of other regulatory proteins. More patients have to be described to confirm the triad of congenital myopathy, neuropathy and deafness as the defining symptom complex for βIV-spectrin deficiency.

βIV Spectrinopathies Cause Profound Intellectual Disability, Congenital Hypotonia, and Motor Axonal Neuropathy

“…Serial electrophysiological studies available in one individual (proband B.II.1) suggest a progressive nature of the neuropathy. Consistent with our findings, the affected person reported by Knierim et al (2017) 18 showed evidence of an axonal motor neuropathy as well. Nevertheless, we did not find evidence of a primary congenital myopathy or a demyelinating neuropathy.…”

“…Our work significantly expands on the neurologic phenotype as well as the underlying mechanism of bIV spectrinopathies. A previous single case report 18 coincides with our findings in describing congenital hypotonia and weakness in an individual with the p.Gln533* variant. Our clinical phenotyping and neurophysiological studies in multiple affected individuals with a variety of pathogenic SPTBN4 variants suggests that weakness is primarily due to severe motor axonal neuropathy and neuronopathy as opposed to a myopathy.…”

“…In contrast, variants p.Gln605*, p.Trp903*, p.Glu1274*, and p.Gln1277Argfs*4 failed to localize at the AIS (Figures 2B and 2E). The previously reported truncation variant, p.Gln533*, 18 also failed to be clustered at the AIS ( Figure 2C). Variants p.Arg504Gln, p.Arg2435Cys, and p.Ala2485Leufs* 31 were still properly targeted to the AIS (Figures 2D and 2E).…”

“…13 A variety of ''quivering'' mice with spontaneous or targeted mutations in Sptbn4 have been reported and studied. [14][15][16][17] Human pathogenic variants in SPTBN4 (MIM:606214) were limited to a single recent case report of an individual with congenital myop-athy, neuropathy, and deafness (CMND [MIM: 617519]), 18 but how this variant causes disease remains unknown. We recently identified six individuals with pathogenic variants of SPTBN4 and similar neurological phenotypes.…”

Spectrin-based pathways underlying electrical and mechanical dysfunction in cardiac disease

“…In a similar vein, genome-wide association studies have uncovered ANK3 (encodes for spectrin-associated AnkG) as a susceptibility locus for human bipolar disorder [60] while mutations in ANK3 have been linked to broad spectrum neurological disorders including autism [61, 62]. More recently, it has been reported that a homozygous nonsense mutation in SPTBN4 (encoding β IV -spectrin) is a novel candidate disease gene for congenital myopathy, neuropathy, and deafness in a consanguineous Kurdish family [63]. …”