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

作者：Knierim Ellen; Gill Esther; Seifert Franziska; Morales Gonzalez Susanne; Unudurthi Sathya D; Hund Thomas J; Stenzel Werner; Schuelke Markus^*

来源：Human Genetics, 2017, 136(7): 903-910.

DOI：10.1007/s00439-017-1814-7

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 beta IV-spectrin, a non-erythrocytic member of the beta-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 beta IV-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 beta IV-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 beta IV-spectrin deficiency.

• 出版日期2017-7