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. 1994 Jul;94(1):418–421. doi: 10.1172/JCI117339

Isodisomy of chromosome 6 in a newborn with methylmalonic acidemia and agenesis of pancreatic beta cells causing diabetes mellitus.

M J Abramowicz 1, M Andrien 1, E Dupont 1, H Dorchy 1, J Parma 1, L Duprez 1, F D Ledley 1, W Courtens 1, E Vamos 1
PMCID: PMC296325  PMID: 7913714

Abstract

Isodisomy (ID) is a genetic anomaly defined as the inheritance of two copies of the same genetic material from one parent. ID in an offspring is a rare cause of recessive genetic diseases via inheritance of two copies of a mutated gene from one carrier parent. We studied a newborn female with a mut(o) of methylmalonic acidemia and complete absence of insulin-producing beta cells in otherwise normal-appearing pancreatic islets, causing insulin-dependent diabetes mellitus. The patient died 2 wk after birth. Serotyping of the HLA antigens, DNA typing of HLA-B and HLA class II loci, study of polymorphic DNA markers of chromosome 6, and cytogenetic analysis demonstrated paternal ID, involving at least a 25-centiMorgan portion of the chromosome pair that encompasses the MHC. ID probably caused methylmalonic acidemia by duplication of a mutated allele of the corresponding gene on the chromosome 6 inherited from the father. It is also very likely that ID was etiologically related to the agenesis of beta cells and consequent insulin-dependent diabetes mellitus in our patient. We thus speculate on the existence of a gene on chromosome 6 involved in beta cell differentiation.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allison J., Campbell I. L., Morahan G., Mandel T. E., Harrison L. C., Miller J. F. Diabetes in transgenic mice resulting from over-expression of class I histocompatibility molecules in pancreatic beta cells. Nature. 1988 Jun 9;333(6173):529–533. doi: 10.1038/333529a0. [DOI] [PubMed] [Google Scholar]
  2. Andrien M., Tiercy J. M., Defleur V., Bouillenne C., Toungouz M., Jeannet M., Dupont E. HLA-B locus DNA typing: detection of B*7801 and seven additional alleles by BW6-specific exon 2 amplification. Tissue Antigens. 1993 Nov;42(5):480–487. doi: 10.1111/j.1399-0039.1993.tb02192.x. [DOI] [PubMed] [Google Scholar]
  3. Blum D., Dorchy H., Mouraux T., Vamos E., Mardens Y., Kumps A., De Prez C., Heimann P., Fowler B., Baumgartner R. Congenital absence of insulin cells in a neonate with diabetes mellitus and mutase-deficient methylmalonic acidaemia. Diabetologia. 1993 Apr;36(4):352–357. doi: 10.1007/BF00400240. [DOI] [PubMed] [Google Scholar]
  4. Dorchy H., Ooms H., Loeb H. Permanent neonatal diabetes mellitus: a case report with plasma insulin studies. Z Kinderheilkd. 1975;118(4):271–281. doi: 10.1007/BF00492333. [DOI] [PubMed] [Google Scholar]
  5. Engel E. A new genetic concept: uniparental disomy and its potential effect, isodisomy. Am J Med Genet. 1980;6(2):137–143. doi: 10.1002/ajmg.1320060207. [DOI] [PubMed] [Google Scholar]
  6. Engel E. Uniparental disomy revisited: the first twelve years. Am J Med Genet. 1993 Jul 1;46(6):670–674. doi: 10.1002/ajmg.1320460613. [DOI] [PubMed] [Google Scholar]
  7. Hejtmancik J. F., Black S., Harris S., Ward P. A., Callaway C., Ledbetter D., Morris J., Leech S. H., Pollack M. S. Congenital 21-hydroxylase deficiency as a new deletion mutation. Detection in a proband during subsequent prenatal diagnosis by HLA typing and DNA analysis. Hum Immunol. 1992 Dec;35(4):246–252. doi: 10.1016/0198-8859(92)90006-9. [DOI] [PubMed] [Google Scholar]
  8. Kwiatkowski T. J., Jr, Beaudet A. L., Trask B. J., Zoghbi H. Y. Linkage mapping and fluorescence in situ hybridization of TCTE1 on human chromosome 6p: analysis of dinucleotide polymorphisms on native gels. Genomics. 1991 Aug;10(4):921–926. doi: 10.1016/0888-7543(91)90180-m. [DOI] [PubMed] [Google Scholar]
  9. Ledley F. D., Lumetta M. R., Zoghbi H. Y., VanTuinen P., Ledbetter S. A., Ledbetter D. H. Mapping of human methylmalonyl CoA mutase (MUT) locus on chromosome 6. Am J Hum Genet. 1988 Jun;42(6):839–846. [PMC free article] [PubMed] [Google Scholar]
  10. Orr H. T., Chung M. Y., Banfi S., Kwiatkowski T. J., Jr, Servadio A., Beaudet A. L., McCall A. E., Duvick L. A., Ranum L. P., Zoghbi H. Y. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet. 1993 Jul;4(3):221–226. doi: 10.1038/ng0793-221. [DOI] [PubMed] [Google Scholar]
  11. Pfizenmaier K., Scheurich P., Schlüter C., Krönke M. Tumor necrosis factor enhances HLA-A,B,C and HLA-DR gene expression in human tumor cells. J Immunol. 1987 Feb 1;138(3):975–980. [PubMed] [Google Scholar]
  12. Sarvetnick N., Liggitt D., Pitts S. L., Hansen S. E., Stewart T. A. Insulin-dependent diabetes mellitus induced in transgenic mice by ectopic expression of class II MHC and interferon-gamma. Cell. 1988 Mar 11;52(5):773–782. doi: 10.1016/0092-8674(88)90414-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Thorsby E., Rønningen K. S. Particular HLA-DQ molecules play a dominant role in determining susceptibility or resistance to type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1993 May;36(5):371–377. doi: 10.1007/BF00402270. [DOI] [PubMed] [Google Scholar]
  14. Welch T. R., Beischel L. S., Choi E., Balakrishnan K., Bishof N. A. Uniparental isodisomy 6 associated with deficiency of the fourth component of complement. J Clin Invest. 1990 Aug;86(2):675–678. doi: 10.1172/JCI114760. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Wilkie P. J., Polymeropoulos M. H., Trent J. M., Small K. W., Weber J. L. Genetic and physical map of 11 short tandem repeat polymorphisms on human chromosome 6. Genomics. 1993 Jan;15(1):225–227. doi: 10.1006/geno.1993.1042. [DOI] [PubMed] [Google Scholar]
  16. Zoghbi H. Y., Jodice C., Sandkuijl L. A., Kwiatkowski T. J., Jr, McCall A. E., Huntoon S. A., Lulli P., Spadaro M., Litt M., Cann H. M. The gene for autosomal dominant spinocerebellar ataxia (SCA1) maps telomeric to the HLA complex and is closely linked to the D6S89 locus in three large kindreds. Am J Hum Genet. 1991 Jul;49(1):23–30. [PMC free article] [PubMed] [Google Scholar]

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