Human Genetics

, Volume 136, Issue 7, pp 903–910 | Cite as

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

  • Ellen Knierim
  • Esther Gill
  • Franziska Seifert
  • Susanne Morales-Gonzalez
  • Sathya D. Unudurthi
  • Thomas J. Hund
  • Werner Stenzel
  • Markus Schuelke
Original Investigation


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.



The authors would like to thank the patient and his parents for participation in the study.

Authors’ contributions

MS, EK phenotyped the patient and gathered clinical information and material; SMG performed cell culture experiments; EG, FS performed molecular genetics experiments; WS performed muscle histology; SDU, TJH provided and prepared the muscle samples of the quivering (qv4J) mouse; MS performed homozygosity mapping, sequence alignment, and bioinformatic analysis of the WES data. EK analyzed and validated the results of the WES data. EK, MS co-authored the first draft of the manuscript and contributed funding. All authors read the final version of the manuscript for intellectual content and gave their permission for publication.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Funding statement

The project was funded by the Charité-Universitätsmedizin Berlin via the “Rahel-Hirsch” Program to EK, the Deutsche Forschungsgemeinschaft (SFB 665 TP C4) to MS, and the NeuroCure Center of Excellence (Exc 257) to MS.

Supplementary material

439_2017_1814_MOESM1_ESM.pdf (643 kb)
Supplementary material 1 (PDF 642 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.NeuroCure Clinical Research CenterCharité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH)BerlinGermany
  2. 2.Department of NeuropediatricsCharité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH)BerlinGermany
  3. 3.Department of NeuropathologyCharité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH)BerlinGermany
  4. 4.The Dorothy M. Davis Heart and Lung Research InstituteThe Ohio State University Wexner Medical CenterColumbusUSA
  5. 5.Department of Biomedical Engineering, College of EngineeringThe Ohio State UniversityColumbusUSA

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