Skip to main content
SpringerLink
Log in

Nemaline myopathy in the Ashkenazi Jewish population is caused by a deletion in the nebulin gene

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Nemaline myopathy (NM) is a neuromuscular disorder that is clinically diverse and can be attributed to mutations in any of several genes. The Ashkenazi Jewish population, which represents a relatively genetically homogeneous group, has an increased frequency of several genetic disorders and has been the beneficiary of genetic screening programs that have reduced the incidence of these diseases. The identification of individuals with NM in this population has prompted a study of its cause. Our study has revealed that five NM patients from five families bear an identical 2,502-bp deletion that lies in the nebulin gene and that includes exon 55 and parts of introns 54 and 55. The absence of this exon results in the generation of a transcript that encodes 35 fewer amino acids. An analysis of the gene frequency of this mutation in a random sample of 4,090 Ashkenazi Jewish individuals has revealed a carrier frequency of one in 108.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1A, B
Fig. 2A, B
Fig. 3

Similar content being viewed by others

References

  • Anderson SL, Coli R, Daly IW, Kichula EA, Rork MJ, Volpi SA, Ekstein J, Rubin BY (2001) Familial dysautonomia is caused by mutations of the IKAP gene. Am J Hum Genet 68:753–758

    Article  CAS  PubMed  Google Scholar 

  • Bargal R, Avidan N, Olender T, Ben Asher E, Zeigler M, Raas-Rothschild A, Frumkin A, Ben-Yoseph O, Friedlender Y, Lancet D, Bach G (2001) Mucolipidosis type IV: novel MCOLN1 mutations in Jewish and non-Jewish patients and the frequency of the disease in the Ashkenazi Jewish population. Hum Mutat 17:397–402

    Article  CAS  PubMed  Google Scholar 

  • Conen PE, Murphy EG, Donohue WL (1963) Light and electron microscopic studies of “myogranules” in a child with hypotonia and muscle weakness. Can Med Assoc J 89:983–986

    CAS  PubMed  Google Scholar 

  • Donner K, Ollikainen M, Ridanpaa M, Christen HJ, Goebel HH, Visser M de, Pelin K, Wallgren-Pettersson C (2002) Mutations in the beta-tropomyosin (TPM2) gene—a rare cause of nemaline myopathy. Neuromusc Disord 12:151–158

    Article  PubMed  Google Scholar 

  • Edelmann L, Dong J, Desnick RJ, Kornreich R (2002) Carrier screening for mucolipidosis type IV in the American Ashkenazi Jewish population. Am J Hum Genet 70:1023–1027

    Article  PubMed  Google Scholar 

  • Ekstein J, Katzenstein H (2001) The Dor Yeshorim story: community-based carrier screening for Tay-Sachs disease. Adv Genet 44:297–310

    Article  CAS  PubMed  Google Scholar 

  • Gurgel-Giannetti J, Reed U, Bang ML, Pelin K, Donner K, Marie SK, Carvalho M, Fireman MA, Zanoteli E, Oliveira AS, Zatz M, Wallgren-Pettersson C, Labeit S, Vainzof M (2001) Nebulin expression in patients with nemaline myopathy. Neuromusc Disord 11:154–162

    Article  CAS  PubMed  Google Scholar 

  • Gurgel-Giannetti J, Bang ML, Reed U, Marie S, Zatz M, Labeit S, Vainzof M (2002) Lack of the C-terminal domain of nebulin in a patient with nemaline myopathy. Muscle Nerve 25:747–752

    Article  CAS  PubMed  Google Scholar 

  • Hudson TJ, Stein LD, Gerety SS, Ma J, Castle AB, Silva J, Slonin DK, Baptista R, Kruglyak L, Xu SH, et al (1995) An STS-based map of the human genome. Science 270:1919–1920

    PubMed  Google Scholar 

  • Ilkovski B, Cooper ST, Nowak K, Ryan MM, Yang N, Schnell C, Durling HJ, Roddick LG, Wilkinson I, Kornberg AJ, Collins KJ, Wallace G, Gunning P, Hardeman EC, Laing NG, North KN (2001) Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene. Am J Hum Genet 68:1333–1343

    Article  CAS  PubMed  Google Scholar 

  • Johnston JJ, Kelley RI, Crawford TO, Morton DH, Agarwala R, Koch T, Schaffer AA, Francomano CA, Biesecker LG (2000) A novel nemaline myopathy in the Amish caused by a mutation in troponin T1. Am J Hum Genet 67:814–821

    Article  CAS  PubMed  Google Scholar 

  • Kaback MM (2000) Population-based genetic screening for reproductive counseling: the Tay-Sachs disease model. Eur J Pediatr 159:S192–S195

    CAS  PubMed  Google Scholar 

  • Kruger M, Wright J, Wang K (1991) Nebulin as a length regulator of thin filaments of vertebrate skeletal muscles: correlation of thin filament length, nebulin size, and epitope profile. J Cell Biol 115:97–107

    Google Scholar 

  • Labeit S, Kolmerer B (1995) The complete primary structure of human nebulin and its correlation to muscle structure. J Mol Biol 248:308–315

    CAS  PubMed  Google Scholar 

  • Labeit S, Gibson T, Lakey A, Leonard K, Zeviani M, Knight P, Wardale J, Trinick J (1991) Evidence that nebulin is a protein-ruler in muscle thin filaments. FEBS Lett 282:313–316 (Erratum, FEBS Lett 295:232)

    Article  CAS  PubMed  Google Scholar 

  • Laing NG, Wilton SD, Akkari PA, Dorosz S, Boundy K, Kneebone C, Blumbergs P, White S, Watkins H, Love DR, et al (1995) A mutation in the alpha tropomyosin gene TPM3 associated with autosomal dominant nemaline myopathy NEM1. Nat Genet 9:75–79

    CAS  PubMed  Google Scholar 

  • Li L, Eng C, Desnick RJ, German J, Ellis NA (1998) Carrier frequency of the Bloom syndrome blmAsh mutation in the Ashkenazi Jewish population. Mol Genet Metab 64:286–290

    Article  CAS  PubMed  Google Scholar 

  • Moncman CL, Wang K (2000) Architecture of the thin filament-Z-line junction: lessons from nebulette and nebulin homologies. J Muscle Res Cell Motil 21:153–169

    Article  CAS  PubMed  Google Scholar 

  • North KN, Laing NG, Wallgren-Pettersson C (1997) Nemaline myopathy: current concepts. The ENMC International Consortium and nemaline myopathy. J Med Genet 34:705–713

    CAS  PubMed  Google Scholar 

  • Nowak KJ, Wattanasirichaigoon D, Goebel HH, Wilce M, Pelin K, Donner K, Jacob RL, Hubner C, Oexle K, Anderson JR, Verity CM, North KN, Iannaccone ST, Muller CR, Nurnberg P, Muntoni F, Sewry C, Hughes I, Sutphen R, Lacson AG, Swoboda KJ, Vigneron J, Wallgren-Pettersson C, Beggs AH, Laing NG (1999) Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy. Nat Genet 23:208–212

    CAS  PubMed  Google Scholar 

  • Pelin K, Ridanpaa M, Donner K, Wilton S, Krishnarajah J, Laing N, Kolmerer B, Millevoi S, Labeit S, Chapelle A de la, Wallgren-Petterson C (1997) Refined localization of the genes for nebulin and titin on chromosome 2q allows the assignment of nebulin as a candidate gene for autosomal recessive nemaline myopathy. Eur J Hum Genet 5:229–234

    CAS  PubMed  Google Scholar 

  • Pelin K, Hilpela P, Donner K, Sewry C, Akkari PA, Wilton SD, Wattanasirichaigoon D, Bang ML, Centner T, Hanefeld F, Odent S, Fardeau M, Urtizberea JA, Muntoni F, Dubowitz V, Beggs AH, Laing NG, Labeit S, Chapelle A de la, Wallgren-Pettersson C (1999) Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy. Proc Natl Acad Sci USA 96:2305–2310

    CAS  PubMed  Google Scholar 

  • Pelin K, Donner K, Holmberg M, Jungbluth H, Muntoni F, Wallgren-Pettersson C (2002) Nebulin mutations in autosomal recessive nemaline myopathy: an update. Neuromusc Disord 12:680–686

    Article  PubMed  Google Scholar 

  • Pfuhl M, Winder SJ, Castiglione Morelli MA, Labeit S, Pastore A (1996) Correlation between conformational and binding properties of nebulin repeats. J Mol Biol 257:367–384

    CAS  PubMed  Google Scholar 

  • Roa BB, Savino CV, Richards CS (1999) Ashkenazi Jewish population frequency of the Bloom syndrome gene 2281 delta 6ins7 mutation. Genet Test 3:219–221

    CAS  PubMed  Google Scholar 

  • Ryan MM, Schnell C, Strickland CD, Shield LK, Morgan G, Iannaccone ST, Laing NG, Beggs AH, North KN (2001) Nemaline myopathy: a clinical study of 143 cases. Ann Neurol 50:312–320

    Article  CAS  PubMed  Google Scholar 

  • Samson F, Jong PJ de, Trask BJ, Koza-Taylor P, Speer MC, Potter T, Roses AD, Gilbert JR (1992) Assignment of the human slow skeletal troponin T gene to 19q13.4 using somatic cell hybrids and fluorescence in situ hybridization analysis. Genomics 13:1374–1375

    CAS  PubMed  Google Scholar 

  • Sanoudou D, Beggs AH (2001) Clinical and genetic heterogeneity in nemaline myopathy—a disease of skeletal muscle thin filaments. Trends Mol Med 7:362–368

    Article  CAS  PubMed  Google Scholar 

  • Sewry CA, Brown SC, Pelin K, Jungbluth H, Wallgren-Pettersson C, Labeit S, Manzur A, Muntoni F (2001) Abnormalities in the expression of nebulin in chromosome-2 linked nemaline myopathy. Neuromusc Disord 11:146–153

    Article  CAS  PubMed  Google Scholar 

  • Shih C-L, Chen M-JG, Linse K, Wang K (1997) Molecular contacts between nebulin and actin: cross-linking of nebulin modules to the N-terminus of actin. Biochemistry 36:1814–1825

    Article  CAS  PubMed  Google Scholar 

  • Shy GM, Engel WK, Somers JE, Wanko T (1963) Nemaline myopathy. A new congenital myopathy. Brain 86:793–810

    CAS  PubMed  Google Scholar 

  • Stultz CM, White JV, Smith TF (1993) Structural analysis based on state-space modeling. Protein Sci 2:305–314

    CAS  PubMed  Google Scholar 

  • Stultz CM, Nambudripad R, Lathrop RH, White JV (1997) Predicting protein structure with probabilistic models. Adv Mol Cell Biol 22B:447–506

    CAS  Google Scholar 

  • Sutton VR (2002) Tay-Sachs disease screening and counseling families at risk for metabolic disease. Obstet Gynecol Clin North Am 29:287–296

    PubMed  Google Scholar 

  • Tan P, Briner J, Boltshauser E, Davis MR, Wilton SD, North K, Wallgren-Pettersson C, Laing NG (1999) Homozygosity for a nonsense mutation in the alpha-tropomyosin slow gene TPM3 in a patient with severe infantile nemaline myopathy. Neuromusc Disord 9:573–579

    CAS  PubMed  Google Scholar 

  • Tiso N, Rampoldi L, Pallavicini A, Zimbello R, Pandolfo D, Valle G, Lanfranchi G, Danieli GA (1997) Fine mapping of five human skeletal muscle genes: alpha-tropomyosin, beta-tropomyosin, troponin-I slow-twitch, troponin-I fast-twitch, and troponin-C fast. Biochem Biophys Res Commun 230:347–350

    Article  CAS  PubMed  Google Scholar 

  • Ueyama H, Inazawa J, Ariyama T, Nishino H, Ochiai Y, Ohkubo I, Miwa T (1995) Reexamination of chromosomal loci of human muscle actin genes by fluorescence in situ hybridization. Jpn J Hum Genet 40:145–148

    CAS  PubMed  Google Scholar 

  • Wallgren-Pettersson C (1990) Congenital nemaline myopathy: a longitudinal study. Commentationes Physico-Mathematicae 111:1–102

    Google Scholar 

  • Wallgren-Pettersson C, Laing N (1996) 40th ENMC Sponsored International Workshop: Nemaline Myopathy. 2–4 February 1996, Naarden, The Netherlands. Neuromusc Disord 6:389–391

    Article  CAS  PubMed  Google Scholar 

  • Wallgren-Pettersson C, Laing NG (2000) Report of the 70th ENMC International Workshop: Nemaline Myopathy. 11–13 June 1999, Naarden, The Netherlands. Neuromusc Disord 10:299–306

    Article  CAS  PubMed  Google Scholar 

  • Wallgren-Pettersson C, Laing N (2003) 109th ENMC International Workshop: 5th Workshop on Nemaline Myopathy, 11–13 October 2002, Naarden, The Netherlands. Neuromusc Disord 13:501

    Article  PubMed  Google Scholar 

  • Wallgren-Pettersson C, Pelin K, Hilpela P, Donner K, Porfirio B, Graziano C, Swoboda KJ, Fardeau M, Urtizberea JA, Muntoni F, Sewry C, Dubowitz V, Iannaccone S, Minetti C, Pedemonte M, Seri M, Cusano R, Lammens M, Castagna-Sloane A, Beggs AH, Laing NG, Chapelle A de la (1999) Clinical and genetic heterogeneity in autosomal recessive nemaline myopathy. Neuromusc Disord 9:564–572

    CAS  PubMed  Google Scholar 

  • Wang K, Knipfer M, Huang QQ, Heerden A van, Hsu LC, Gutierrez G, Quian XL, Stedman H (1996) Human skeletal muscle nebulin sequence encodes a blueprint for thin filament architecture. Sequence motifs and affinity profiles of tandem repeats and terminal SH3. J Biol Chem 271:4304–4314

    CAS  PubMed  Google Scholar 

  • White JV, Stultz CM, Smith TF (1994) Protein classification by stochastic modeling and optimal filtering of amino-acid sequences. Math Biosci 119:35–75

    Article  CAS  PubMed  Google Scholar 

  • Wilton SD, Eyre H, Akkari PA, Watkins HC, MacRae C, Laing NG, Callen DC (1995) Assignment of the human α-tropomyosin gene TPM3 to 1q22→q23 by fluorescence in situ hybridization. Cytogenet Cell Genet 68:122–124

    CAS  PubMed  Google Scholar 

  • Wright J, Huang QQ, Wang K (1993) Nebulin is a full-length template of actin filaments in the skeletal muscle sarcomere: an immunoelectron microscopic study of its orientation and span with site-specific monoclonal antibodies. J Muscle Res Cell Motil 14:476–483

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was funded by grants from the DYHM Foundation and Dor Yeshorim, The Committee for Prevention of Jewish Diseases. We thank Hershel Meisels for his valuable assistance and Dr. R. Kandpal for helpful comments and discussion.

Author information

Authors and Affiliations

  1. Department of Biological Sciences, Fordham University, Larkin Hall 160, Bronx, NY 10458, USA

    Sylvia L. Anderson, Mary C. Donnelly, Erin M. Keefe, Nicole R. Toto, Lauretta A. LeVoci & Berish Y. Rubin

  2. Dor Yeshorim, The Committee for Prevention of Jewish Diseases, Brooklyn, N.Y., USA

    Josef Ekstein

Authors
  1. Sylvia L. Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Josef Ekstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mary C. Donnelly
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Erin M. Keefe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nicole R. Toto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lauretta A. LeVoci
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Berish Y. Rubin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Berish Y. Rubin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Anderson, S.L., Ekstein, J., Donnelly, M.C. et al. Nemaline myopathy in the Ashkenazi Jewish population is caused by a deletion in the nebulin gene. Hum Genet 115, 185–190 (2004). https://doi.org/10.1007/s00439-004-1140-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-004-1140-8

Keywords

Search

Navigation