• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of ajhgLink to Publisher's site
Am J Hum Genet. May 1996; 58(5): 963–970.
PMCID: PMC1914608

Autosomal recessive Wolfram syndrome associated with an 8.5-kb mtDNA single deletion.


Wolfram syndrome (MIM 222300) is characterized by optic atrophy, diabetes mellitus, diabetes insipidus, neurosensory hearing loss, urinary tract abnormalities, and neurological dysfunction. The association of clinical manifestations in tissues and organs unrelated functionally or embryologically suggested the possibility of a mitochondrial implication in the disease, which has been demonstrated in two sporadic cases. Nonetheless, familial studies suggested an autosomal recessive mode of transmission, and recent data demonstrated linkage with markers on the short arm of human chromosome 4. The patient reported here, as well as her parents and unaffected sister, carried a heteroplasmic 8.5-kb deletion in mtDNA. The deletion accounted for 23% of mitochondrial genomes in lymphocytes from the patient and approximately 5% in the tissues studied from members of her family. The presence of the deletion in the patient in a proportion higher than in her unaffected parents suggests a putative defect in a nuclear gene that acts at the mitochondrial level.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.5M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • 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]
  • Ballinger SW, Shoffner JM, Hedaya EV, Trounce I, Polak MA, Koontz DA, Wallace DC. Maternally transmitted diabetes and deafness associated with a 10.4 kb mitochondrial DNA deletion. Nat Genet. 1992 Apr;1(1):11–15. [PubMed]
  • 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]
  • 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]
  • 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]
  • Clayton DA. Replication of animal mitochondrial DNA. Cell. 1982 Apr;28(4):693–705. [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]
  • 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]
  • 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]
  • Dunbar DR, Moonie PA, Swingler RJ, Davidson D, Roberts R, Holt IJ. Maternally transmitted partial direct tandem duplication of mitochondrial DNA associated with diabetes mellitus. Hum Mol Genet. 1993 Oct;2(10):1619–1624. [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]
  • 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]
  • Holt IJ, Harding AE, Morgan-Hughes JA. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature. 1988 Feb 25;331(6158):717–719. [PubMed]
  • Holt IJ, Harding AE, Petty RK, Morgan-Hughes JA. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet. 1990 Mar;46(3):428–433. [PMC free article] [PubMed]
  • Lathrop GM, Lalouel JM, Julier C, Ott J. Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci U S A. 1984 Jun;81(11):3443–3446. [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]
  • 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]
  • Rötig A, Cormier V, Blanche S, Bonnefont JP, Ledeist F, Romero N, Schmitz J, Rustin P, Fischer A, Saudubray JM, et al. Pearson's marrow-pancreas syndrome. A multisystem mitochondrial disorder in infancy. J Clin Invest. 1990 Nov;86(5):1601–1608. [PMC free article] [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]
  • 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]
  • Rustin P, Chretien D, Bourgeron T, Wucher A, Saudubray JM, Rotig A, Munnich A. Assessment of the mitochondrial respiratory chain. Lancet. 1991 Jul 6;338(8758):60–60. [PubMed]
  • Saiz A, Vila N, Muñoz JE, Martí MJ, Graus F, Tolosa E. Síndrome de Wolfram: correlación cliniconeurorradiológica. Neurologia. 1995 Feb;10(2):107–109. [PubMed]
  • Schon EA, Rizzuto R, Moraes CT, Nakase H, Zeviani M, DiMauro S. A direct repeat is a hotspot for large-scale deletion of human mitochondrial DNA. Science. 1989 Apr 21;244(4902):346–349. [PubMed]
  • Shoffner JM, Lott MT, Lezza AM, Seibel P, Ballinger SW, Wallace DC. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell. 1990 Jun 15;61(6):931–937. [PubMed]
  • Shoffner JM, Lott MT, Voljavec AS, Soueidan SA, Costigan DA, Wallace DC. Spontaneous Kearns-Sayre/chronic external ophthalmoplegia plus syndrome associated with a mitochondrial DNA deletion: a slip-replication model and metabolic therapy. Proc Natl Acad Sci U S A. 1989 Oct;86(20):7952–7956. [PMC free article] [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]
  • Suomalainen A, Majander A, Haltia M, Somer H, Lönnqvist J, Savontaus ML, Peltonen L. Multiple deletions of mitochondrial DNA in several tissues of a patient with severe retarded depression and familial progressive external ophthalmoplegia. J Clin Invest. 1992 Jul;90(1):61–66. [PMC free article] [PubMed]
  • Swift RG, Sadler DB, Swift M. Psychiatric findings in Wolfram syndrome homozygotes. Lancet. 1990 Sep 15;336(8716):667–669. [PubMed]
  • Tagle DA, Blanchard-McQuate KL, Collins FS. Dinucleotide repeat polymorphism in the Huntington's disease region at the D4S43 locus. Hum Mol Genet. 1992 Jun;1(3):215–215. [PubMed]
  • Tritschler HJ, Andreetta F, Moraes CT, Bonilla E, Arnaudo E, Danon MJ, Glass S, Zelaya BM, Vamos E, Telerman-Toppet N, et al. Mitochondrial myopathy of childhood associated with depletion of mitochondrial DNA. Neurology. 1992 Jan;42(1):209–217. [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]
  • 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]
  • Zeviani M, Servidei S, Gellera C, Bertini E, DiMauro S, DiDonato S. An autosomal dominant disorder with multiple deletions of mitochondrial DNA starting at the D-loop region. Nature. 1989 May 25;339(6222):309–311. [PubMed]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...