• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. Apr 1, 1996; 97(7): 1570–1576.
PMCID: PMC507219

A nuclear defect in the 4p16 region predisposes to multiple mitochondrial DNA deletions in families with Wolfram syndrome.


Wolfram syndrome is a progressive neurodegenerative disorder transmitted in an autosomal recessive mode. We report two Wolfram syndrome families harboring multiple deletions of mitochondrial DNA. The deletions reached percentages as high as 85-90% in affected tissues such as the central nervous system of one patient, while in other tissues from the same patient and from other members of the family, the percentages of deleted mitochondrial DNA genomes were only 1-10%. Recently, a Wolfram syndrome gene has been linked to markers on 4p16. In both families linkage between the disease locus and 4p16 markers gave a maximum multipoint lod score of 3.79 at theta = 0 (P<0.03) with respect to D4S431. In these families, the syndrome was caused by mutations in this nucleus-encoded gene which deleteriously interacts with the mitochondrial genome. This is the first evidence of the implication of both genomes in a recessive disease.

Full Text

The Full Text of this article is available as a PDF (274K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Borgna-Pignatti C, Marradi P, Pinelli L, Monetti N, Patrini C. Thiamine-responsive anemia in DIDMOAD syndrome. J Pediatr. 1989 Mar;114(3):405–410. [PubMed]
  • Swift RG, Sadler DB, Swift M. Psychiatric findings in Wolfram syndrome homozygotes. Lancet. 1990 Sep 15;336(8716):667–669. [PubMed]
  • Swift RG, Perkins DO, Chase CL, Sadler DB, Swift M. Psychiatric disorders in 36 families with Wolfram syndrome. Am J Psychiatry. 1991 Jun;148(6):775–779. [PubMed]
  • Cremers CW, Wijdeveld PG, Pinckers AJ. Juvenile diabetes mellitus, optic atrophy, hearing loss, diabetes insipidus, atonia of the urinary tract and bladder, and other abnormalities (Wolfram syndrome). A review of 88 cases from the literature with personal observations on 3 new patients. Acta Paediatr Scand Suppl. 1977;(264):1–16. [PubMed]
  • Fraser FC, Gunn T. Diabetes mellitus, diabetes insipidus, and optic atrophy. An autosomal recessive syndrome? J Med Genet. 1977 Jun;14(3):190–193. [PMC free article] [PubMed]
  • Polymeropoulos MH, Swift RG, Swift M. Linkage of the gene for Wolfram syndrome to markers on the short arm of chromosome 4. Nat Genet. 1994 Sep;8(1):95–97. [PubMed]
  • Bundey S, Poulton K, Whitwell H, Curtis E, Brown IA, Fielder AR. Mitochondrial abnormalities in the DIDMOAD syndrome. J Inherit Metab Dis. 1992;15(3):315–319. [PubMed]
  • Rötig A, Cormier V, Chatelain P, Francois R, Saudubray JM, Rustin P, Munnich A. Deletion of mitochondrial DNA in a case of early-onset diabetes mellitus, optic atrophy, and deafness (Wolfram syndrome, MIM 222300). J Clin Invest. 1993 Mar;91(3):1095–1098. [PMC free article] [PubMed]
  • Zeviani M, Bresolin N, Gellera C, Bordoni A, Pannacci M, Amati P, Moggio M, Servidei S, Scarlato G, DiDonato S. Nucleus-driven multiple large-scale deletions of the human mitochondrial genome: a new autosomal dominant disease. Am J Hum Genet. 1990 Dec;47(6):904–914. [PMC free article] [PubMed]
  • Yuzaki M, Ohkoshi N, Kanazawa I, Kagawa Y, Ohta S. Multiple deletions in mitochondrial DNA at direct repeats of non-D-loop regions in cases of familial mitochondrial myopathy. Biochem Biophys Res Commun. 1989 Nov 15;164(3):1352–1357. [PubMed]
  • Uncini A, Servidei S, Silvestri G, Manfredi G, Sabatelli M, Di Muzio A, Ricci E, Mirabella M, Di Mauro S, Tonali P. Ophthalmoplegia, demyelinating neuropathy, leukoencephalopathy, myopathy, and gastrointestinal dysfunction with multiple deletions of mitochondrial DNA: a mitochondrial multisystem disorder in search of a name. Muscle Nerve. 1994 Jun;17(6):667–674. [PubMed]
  • Suomalainen A, Kaukonen J, Amati P, Timonen R, Haltia M, Weissenbach J, Zeviani M, Somer H, Peltonen L. An autosomal locus predisposing to deletions of mitochondrial DNA. Nat Genet. 1995 Feb;9(2):146–151. [PubMed]
  • Rustin P, Chretien D, Bourgeron T, Gérard B, Rötig A, Saudubray JM, Munnich A. Biochemical and molecular investigations in respiratory chain deficiencies. Clin Chim Acta. 1994 Jul;228(1):35–51. [PubMed]
  • Goto Y, Nonaka I, Horai S. A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature. 1990 Dec 13;348(6302):651–653. [PubMed]
  • DiDonato S, Zeviani M, Giovannini P, Savarese N, Rimoldi M, Mariotti C, Girotti F, Caraceni T. Respiratory chain and mitochondrial DNA in muscle and brain in Parkinson's disease patients. Neurology. 1993 Nov;43(11):2262–2268. [PubMed]
  • Cottingham RW, Jr, Idury RM, Schäffer AA. Faster sequential genetic linkage computations. Am J Hum Genet. 1993 Jul;53(1):252–263. [PMC free article] [PubMed]
  • Gyapay G, Morissette J, Vignal A, Dib C, Fizames C, Millasseau P, Marc S, Bernardi G, Lathrop M, Weissenbach J. The 1993-94 Généthon human genetic linkage map. Nat Genet. 1994 Jun;7(2 Spec No):246–339. [PubMed]
  • Ott J. Computer-simulation methods in human linkage analysis. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4175–4178. [PMC free article] [PubMed]
  • Casademont J, Barrientos A, Cardellach F, Rötig A, Grau JM, Montoya J, Beltrán B, Cervantes F, Rozman C, Estivill X, et al. Multiple deletions of mtDNA in two brothers with sideroblastic anemia and mitochondrial myopathy and in their asymptomatic mother. Hum Mol Genet. 1994 Nov;3(11):1945–1949. [PubMed]
  • Cormier V, Rotig A, Tardieu M, Colonna M, Saudubray JM, Munnich A. Autosomal dominant deletions of the mitochondrial genome in a case of progressive encephalomyopathy. Am J Hum Genet. 1991 Apr;48(4):643–648. [PMC free article] [PubMed]
  • Cortopassi GA, Arnheim N. Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Res. 1990 Dec 11;18(23):6927–6933. [PMC free article] [PubMed]
  • Corral-Debrinski M, Horton T, Lott MT, Shoffner JM, Beal MF, Wallace DC. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nat Genet. 1992 Dec;2(4):324–329. [PubMed]
  • Polymeropoulos MH, Xiao H, Torrey EF, DeLisi LE, Crow T, Merril CR. Search for a genetic event in monozygotic twins discordant for schizophrenia. Psychiatry Res. 1993 Jul;48(1):27–36. [PubMed]
  • Hsieh CL, Donlon TA, Darras BT, Chang DD, Topper JN, Clayton DA, Francke U. The gene for the RNA component of the mitochondrial RNA-processing endoribonuclease is located on human chromosome 9p and on mouse chromosome 4. Genomics. 1990 Mar;6(3):540–544. [PubMed]
  • Tiranti V, Rossi E, Ruiz-Carrillo A, Rossi G, Rocchi M, DiDonato S, Zuffardi O, Zeviani M. Chromosomal localization of mitochondrial transcription factor A (TCF6), single-stranded DNA-binding protein (SSBP), and endonuclease G (ENDOG), three human housekeeping genes involved in mitochondrial biogenesis. Genomics. 1995 Jan 20;25(2):559–564. [PubMed]
  • Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, et al. Sequence and organization of the human mitochondrial genome. Nature. 1981 Apr 9;290(5806):457–465. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • MedGen
    Related information in MedGen
  • OMIM
    OMIM record citing PubMed
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...