Skip to main content

Advertisement

Springer Nature Link
Log in

SNTG1, the gene encoding γ1-syntrophin: a candidate gene for idiopathic scoliosis

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

Abstract

Idiopathic scoliosis (IS) affects approximately 2%–3% of the population and has a heritable component. The genetics of this disorder are complex. Here, we describe a family in which a pericentric inversion of chromosome 8 co-segregates with IS. We have used fluorescence in situ hybridization to identify cloned DNAs that span the breakpoints on the two arms of the chromosome. We have identified a bacterial artificial chromosome (BAC) of 150 kb that crosses the q-arm breakpoint and a BAC of 120 kb that crosses the p-arm breakpoint. The complete genomic DNA sequence of these BACs has been analyzed to identify candidate genes and to localize further the precise breakpoints. This has revealed that the p-arm break does not interrupt any known gene and occurs in a region of highly repetitive sequence elements. On the q-arm, the break occurs between exons 10 and 11 of the γ-1 syntrophin (SNTG1) gene. Syntrophins are a group of cytoplasmic peripheral membrane proteins that associate directly with dystrophin, the Duchenne muscular dystrophy gene; γ1-syntrophin has been shown to be a neuronal cell-specific protein. Mutational analysis of SNTG1 exons in 152 sporadic IS patients has revealed a 6-bp deletion in exon 10 of SNTG1 in one patient and a 2-bp insertion/deletion mutation occurring in a polypyrimidine tract of intronic sequence 20 bases upstream of the SNTG1 exon 5 splice site in two patients. These changes were not seen in a screen of 480 control chromosomes. Genomic DNAs from seven affected individuals within the family of a patient carrying the 6-bp deletion were typed to determine whether the alteration co-segregated with IS. The deletion was only observed in five out of these seven individuals. Thus, although genetic heterogeneity or multiple alleles cannot be ruled out, the 6-bp deletion does not consistently co-segregate with the disease in this family.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1A–C
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Ahn AH, Freener CA, Gussoni E, Yoshida M, Ozawa E, Kunkel LM (1996) The three human syntrophin genes are expressed in diverse tissues, have distinct chromosomal locations, and each bind to dystrophin and its relatives. J Biol Chem 271:2724–2730

    Article  CAS  PubMed  Google Scholar 

  • Beals RK (1973) Nosologic and genetic aspects of scoliosis. Clin Orthop 93:23–32

    CAS  PubMed  Google Scholar 

  • Berven S, Fairbank J, Carr A, Sadovoy M, Tregubova I, Zaidman A (1997) On the genetics of spinal asymmetry and adolescent idiopathic scoliosis patterns of deformity and heredity. J Bone Joint Surg Am 79:452

    Article  Google Scholar 

  • Boyd H, Kaste J, Hovie E, Ritanen-Mohammed UM, Kaariainen H, Chapelle A de la, Lehesjoki AE (1994) Familial pericentric inversion inv(8)(p23q11). J Med Genet 31:201–205

    CAS  PubMed  Google Scholar 

  • Brownstein BH, Silverman GA, Little RD, Burke DT, Korsmeyer SJ, Schlessinger D, Olson MV (1989) Isolation of single-copy human genes from a library of yeast artificial chromosome clones. Science 244:1348–1351

    CAS  PubMed  Google Scholar 

  • Bugge M, Bruun-Petersen G, Brondum-Nielsen K, Friedrich U, Hansen J, Jensen G, Jensen PKA, Kristoffersson U, Lundsteen C, Neibuhr E, Rasmussen KR, Rasmussen K, Tommerup N (2002) Disease associated balanced chromosome rearrangements: a resource for large scale genotype-phenotype delineation in man. J Med Genet 37:858–865

    Article  Google Scholar 

  • Burwell RG, Cole AA, Cook TA (1992) Pathogenesis of idiopathic scoliosis: the Nottingham concept. Acta Orthop Belg 58:33–58

    PubMed  Google Scholar 

  • Byl NN, Gray JM (1993) Complex balance reactions in different sensory conditions: adolescents with and without idiopathic scoliosis. J Orthop Res 11:215–227

    CAS  PubMed  Google Scholar 

  • Chan V, Gardian CYF, Luk KDK, Yip B, Lee M-K, Wong M-S, Lu DDS, Chan T-K (2002) Putative loci for idiopathic scoliosis on chromosome 19p. Am J Hum Genet 71:401–406

    Article  CAS  PubMed  Google Scholar 

  • Chen PQ, Wang JL, Tsuang YH, Liao, TL, Huang PI, Hang YS (1998) The postural stability control and gait pattern of idiopathic scoliosis adolescents. Clin Biochem 13:52–58

    Article  Google Scholar 

  • Cobb JR (1948) Outline for the study of scoliosis. In: American Academy of Orthopaedic Surgeons (eds) Instructional course lectures, vol 5. American Academy of Orthopaedic Surgeons, Ann Arbor, pp 261–275

  • Collins FS (1995) Positional cloning moves from perditional to traditional. Nat Genet 9:347–350

    CAS  PubMed  Google Scholar 

  • Coolidge CJ, Seely RJ, Patton JG (1997) Functional analysis of the polypyrimidine tract in pre-mRNA splicing. Nucleic Acids Res 25:888–896

    Article  CAS  PubMed  Google Scholar 

  • Do T (2002) Orthopedic management of the muscular dystrophies. Curr Opin Pediatr 14:50–53

    Article  PubMed  Google Scholar 

  • Dubousset J, Queneau P, Thillard M (1983) Experimental scoliosis induced by pineal and diencephalic lesions in young chickens: its relation with clinical findings. Orthop Trans 7:7

    Google Scholar 

  • European Polycystic Kidney Disease Consortium (1994) The polycyctic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. Cell 77:881–894

    PubMed  Google Scholar 

  • Fantes J, Redeker B, Breen M, Boyle S, Brown J, Fletcher J, Jones S, Bickmore W, Fukushima Y, Mannens M, et al (1995) Aniridia-associated cytogenetic rearrangements suggest that a position effect may cause the mutant phenotype. Hum Mol Genet 4:415–422

    CAS  PubMed  Google Scholar 

  • Fountain JW, Wallace MR, Bruce MA, Seizinger BR, Menon AG, Gusella JF, Michels VV, Schmidt MA, Dewald GW, Collins FS (1989) Physical mapping of a translocation breakpoint in neurofibromatosis. Science 244:1085–1087

    CAS  PubMed  Google Scholar 

  • Frendewey D, Keller W (1985) Stepwise assembly of a pre-mRNA splicing complex requires U-snRNPs and specific intron sequences. Cell 42:355–367

    CAS  PubMed  Google Scholar 

  • Harrington PR (1977) The etiology of idiopathic scoliosis. Clin Orthop 126:17–25

    PubMed  Google Scholar 

  • Hensinger RN, MacEwen GD (1976) Spinal deformity associated with heritable neurological conditions: spinal muscular atrophy, Friedreich’s ataxia, familial dysautonomia, and Charcot-Marie-Tooth disease. J Bone Joint Surg Am 58:13–24

    CAS  PubMed  Google Scholar 

  • Hogan A, Shepherd L, Chabot J, Quenneville S, Prescott SM, Topham MK, Gee SH (2001) Interaction of γ1-syntrophin with diacylglycerol kinase-ζ. J Biol Chem 276:26526–26533

    Article  CAS  PubMed  Google Scholar 

  • Inoue M, Minami S, Kitahara H, Otsuka Y, Nakata Y, Takaso M, Moriya H (1998) Idiopathic scoliosis in twins studied by DNA fingerprinting: the incidence and type of scoliosis.J Bone Joint Surg Br 80:212–217

    Article  CAS  PubMed  Google Scholar 

  • Jacobs PA, Buckton KE, Cunningham C, Newton M (1974) An analysis of the breakpoints of structural rearrangements in man. J Med Genet 11:50–64

    CAS  PubMed  Google Scholar 

  • Justice CM, Miller NH, Marosy B, Zhand J, Wilson AF (2002) Identification of loci involved in familial idiopathic scoliosis. Program No. 1577, 2002 ASHG Annual Meeting

  • Kesling K, Reinker KA (1997) Scoliosis in twins. Spine 22:2009–2015

    CAS  PubMed  Google Scholar 

  • Kleczkowska A, Fryn JP, Berghe H van den (1987) Pericentric inversions in man: personal experience and review of the literature. Hum Genet 75:333–338

    Google Scholar 

  • Lee FJ (1992) Modified protocol for yeast DNA mini-preparation. Biotechniques 12:677

    CAS  PubMed  Google Scholar 

  • Lengauer C, Green ED, Cremer T (1992) Fluorescence in situ hybridization of YAC clones after Alu-PCR amplification. Genomics 13:826–828

    CAS  PubMed  Google Scholar 

  • Lonstein JE (1994) Adolescent idiopathic scoliosis. Lancet 344:1407–1412

    Article  CAS  PubMed  Google Scholar 

  • Lowe TG, Edgar M, Margulies JY, Miller NH, Raso VJ, Reinker KA, Rivard CH (2000) Etiology of idiopathic scoliosis: current trends in research. J Bone Joint Surg Am 82:1157–1168

    Google Scholar 

  • Machida M, Murai I, Miyashita Y, Dubousset J, Yamada T, Kimura J (1999) Pathogenesis of idiopathic scoliosis. Experimental study in rats. Spine 24:1985–1989

    Article  CAS  PubMed  Google Scholar 

  • Maguire J, Madigan R, Wallace S, Leppanen R, Draper V (1993) Intraoperative long-latency reflex activity in idiopathic scoliosis demonstrates abnormal central processing. A possible cause of idiopathic scoliosis. Spine 18:1621–1626

    CAS  PubMed  Google Scholar 

  • Manzoni D, Miele F (2002) Vestibular mechanisms involved in idiopathic scoliosis. Arch Ital Biol 140:67–80

    CAS  PubMed  Google Scholar 

  • Nault M-L, Allard P, Hinse S, Blanc RL, Caron O, Labelle H, Sadeghi H (2002) Relations between standing stability and body posture parameters in adolescent idiopathic scoliosis. Spine 27:1911–1917

    Article  PubMed  Google Scholar 

  • O’Kelly C, Wang X, Raso J, Moreau M, Mahood J, Zhao J, Bagnall K (1999) The production of scoliosis after pinealectomy in young chickens, rats, and hamsters. Spine 24:35–43

    Article  CAS  PubMed  Google Scholar 

  • Piluso G, Mirabella M, Ricci E, Belsito A, Abbondanza C, Servidei S, Puca AA, Tonali P, Puca GA, Nigro V (2000) Gamma1- and gamma2-syntrophins, two novel dystrophin-binding proteins localized in neuronal cells. J Biol Chem 275:15851–15860

    Article  CAS  PubMed  Google Scholar 

  • Pincott JR, Davies JS, Taffs LF (1984) Scoliosis caused by section of dorsal spinal nerve roots. J Bone Joint Surg Br 66:27–29

    CAS  PubMed  Google Scholar 

  • Riseboroug EJ, Wynne-Davies R (1973) A genetic survey of idiopathic scoliosis in Boston, Massachusetts. J Bone Joint Surg Am 55:974–982

    PubMed  Google Scholar 

  • Rogala EJ, Drummond DS, Gurr J (1978) Scoliosis: incidence and natural history: a prospective epidemiological study. J Bone Joint Surg Am 60:173–176

    CAS  PubMed  Google Scholar 

  • Ruskin B, Green MR (1985) Role of the 3’ splice site consensus sequence in mammalian pre-mRNA splicing. Nature 317:732–734

    CAS  PubMed  Google Scholar 

  • Salehi LB, Mangino M, De Serio S, De Cicco D, Capon F, Semprini S, Pizzuti A, Novelli G, Dallapiccola B (2002) Assignment of a locus for autosomal dominant idiopathic scoliosis (IS) to human chromosome 17p11. Hum Genet 111:401–404

    Article  CAS  PubMed  Google Scholar 

  • Sillence DO, Barlow KK, Cole WG, Dietrich S, Garber AP, Rimoin DL (1986) Osteogenesis imperfecta type III: delineation of the phenotype with reference to genetic heterogeneity. Am J Med Genet 23:821–832

    CAS  PubMed  Google Scholar 

  • Szappanos L, Balogh E, Szeszak F, Olah E, Nagy Z, Szepesi K (1997) Idiopathic scoliosis—new surgical methods or search for the reasons. Acta Chir Hung 36:343–345

    CAS  PubMed  Google Scholar 

  • Tierney I, Axworthy D, Smith L, Ratcliffe SG (1984) Balanced rearrangements of the autosomes: results of a longitudinal study of a newborn survey. J Med Genet 21:45–51

    CAS  PubMed  Google Scholar 

  • Thillard MJ (1959) Vertebral column deformities following epiphysectomy in the chick. C R Hebd Seances Acad Sci 248:1238–1240

    CAS  PubMed  Google Scholar 

  • Walker JL, Nelson KR, Stevens DB, Lubicky JP, Ogden JA, VandenBrink KD (1994) Spinal deformity in Charcot-Marie-Tooth disease. Spine 19:1044–1047

    CAS  PubMed  Google Scholar 

  • Warburton D (1991) De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints. Am J Hum Genet 49:995–1013

    CAS  PubMed  Google Scholar 

  • Weinstein SL (1991) Advances in the diagnosis and management of adolescent idiopathic scoliosis. J Pediatr Orthop 11:561–563

    Google Scholar 

  • Wise CA, Barnes R, Gillum J, Herring JA, Bowcock AM, Lovett M (2000) Localization of susceptibility to familial idiopathic scoliosis. Spine 25:2372–2380

    Article  CAS  PubMed  Google Scholar 

  • Womack M, Khodakhah K (2002) Active contribution of dendrites to the tonic and trimodal patterns of activity in cerebellar Purkinje neurons. J Neurosci 22:10603–10612

    CAS  PubMed  Google Scholar 

  • Yamada K, Yamamoto H, Nakagawa Y, Tezuka A, Tamura T, Kawata S (1984) Etiology of idiopathic scoliosis. Clin Orthop 184:50–57

    PubMed  Google Scholar 

  • Yamashita T, Kanaya K, Kawaguchi S, Murakami T, Yokogushi K (2001) Prediction of progression of spinal deformity in Duchenne muscular dystrophy: a preliminary report. Spine 26:223–226

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA

    Stavros Bashiardes, Rose Veile, Missy Allen, Anne M. Bowcock & Michael Lovett

  2. Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, USA

    Mathew Dobbs

  3. Department of Orthopaedic Surgery, The University of Iowa Hospitals and Clinics, Iowa City, IA, USA

    Jose A. Morcuende

  4. Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX, USA

    Carol A. Wise, Lazlos Szappanos & John A. Herring

Authors
  1. Stavros Bashiardes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rose Veile
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Missy Allen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carol A. Wise
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mathew Dobbs
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jose A. Morcuende
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lazlos Szappanos
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. John A. Herring
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Anne M. Bowcock
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Michael Lovett
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Lovett.

Electronic Supplementary Material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bashiardes, S., Veile, R., Allen, M. et al. SNTG1, the gene encoding γ1-syntrophin: a candidate gene for idiopathic scoliosis. Hum Genet 115, 81–89 (2004). https://doi.org/10.1007/s00439-004-1121-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-004-1121-y

Keywords

Search

Navigation