Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Mutant deoxynucleotide carrier is associated with congenital microcephaly

Nature Genetics volume 32, pages 175–179 (2002)Cite this article

Abstract

The disorder Amish microcephaly (MCPHA) is characterized by severe congenital microcephaly, elevated levels of α-ketoglutarate in the urine and premature death1. The disorder is inherited in an autosomal recessive pattern and has been observed only in Old Order Amish families whose ancestors lived in Lancaster County, Pennsylvania. Here we show, by using a genealogy database and automated pedigree software, that 23 nuclear families affected with MCPHA are connected to a single ancestral couple. Through a whole-genome scan, fine mapping and haplotype analysis, we localized the gene affected in MCPHA to a region of 3 cM, or 2 Mb, on chromosome 17q25. We constructed a map of contiguous genomic clones spanning this region. One of the genes in this region, SLC25A19, which encodes a nuclear mitochondrial deoxynucleotide carrier (DNC)2, contains a substitution that segregates with the disease in affected individuals and alters an amino acid that is highly conserved in similar proteins. Functional analysis shows that the mutant DNC protein lacks the normal transport activity, implying that failed deoxynucleotide transport across the inner mitochondrial membrane causes MCPHA. Our data indicate that mitochondrial deoxynucleotide transport may be essential for prenatal brain growth.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Pedigree of the 16 nuclear affected families screened in this study.
Figure 2: Physical map of the candidate region of 2 Mb associated with MCPHA and bounded by the markers indicated in Table 2b.
Figure 3: Transport assays of wildtype and mutant DNC.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Kelley, R.I., Robinson, D., Puffenberger, E.G., Strauss, K.A. & Morton, D.H. Amish lethal microcephaly: a new metabolic disorder with severe congenital microcephaly and 2-ketoglutaric aciduria. Am. J. Med. Genet. (2002); advanced online publication, 7 June 2002 (doi:10.1002/ajmg 10529).

  2. Dolce, V., Fiermonte, G., Runswick, M.J., Palmieri, F. & Walker, J.E. The human mitochondrial deoxynucleotide carrier and its role in the toxicity of nucleoside antivirals. Proc. Natl Acad. Sci. USA 98, 2284–2288 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Carey, J.C. in Rudolph's Pediatrics (eds Rudolph, A.M., Hoffman, J.I.E. & Rudolph, C.D.) 427–429 (Appleton and Lange, Stamford, CT, 1996).

    Google Scholar 

  4. Weber, J. & Broman, K. Genotyping for human whole-genome scans: past, present, and future. Adv. Genet. 42, 77–96 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Kuhlenbäumer, G. et al. A sequence-ready BAC/PAC contig and partial transcript map of approximately 1.5 Mb in human chromosome 17q25 comprising multiple disease genes. Genomics 62, 242–250 (1999).

    Article  PubMed  Google Scholar 

  6. Kalikin, L.M. et al. An integrated physical and gene map of human distal chromosome 17q24-proximal 17q25 encompassing multiple disease loci. Genomics 57, 36–42 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Risk, J.M. et al. The tylosis esophageal cancer (TOC) locus: more than just a familial cancer gene. Dis. Esophagus 12, 173–176 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Lander, E.S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Makalowska, I., Ryan, J.F. & Baxevanis, A.D. GeneMachine: gene prediction and sequence annotation. Bioinformatics 17, 843–844 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Rosenberg, M.J. et al. Scanning for telomeric deletions and duplications and uniparental disomy using genetic markers in 120 children with malformations. Hum. Genet. 109, 311–318 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Palmieri, F. Mitochondrial carrier proteins. FEBS Lett. 346, 48–54 (1994).

    Article  CAS  PubMed  Google Scholar 

  12. Marchler-Bauer, A. et al. CDD: a database of conserved domain alignments with links to domain three-dimensional structure. Nucleic Acids Res. 30, 281–283 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Agarwala, R., Schäffer, A.A. & Tomlin, J.F. Towards a complete North American Anabaptist Genealogy II: analysis of inbreeding. Hum. Biol. 73, 533–545 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Agarwala, R., Biesecker, L.G., Hopkins, K.A., Francomano, C.A. & Schäffer, A.A. Software for constructing and verifying pedigrees within large genealogies and an application to the Old Order Amish of Lancaster County. Genome Res. 8, 211–221 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. Johnston, J.J. et al. A novel nemaline myopathy in the Amish caused by a mutation in troponin T1. Am. J. Hum. Genet. 67, 814–821 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Koch, T. & Martin, A. Solving Steiner tree problems in graphs to optimality. Networks 32, 207–232 (1998).

    Article  Google Scholar 

  17. Biesecker, L.G. et al. Detection of a subtle rearrangement of chromosome 22 using molecular techniques. Am. J. Med. Genet. 58, 389–394 (1995).

    Article  CAS  PubMed  Google Scholar 

  18. Cottingham, R.W. Jr, Idury, R.M. & Schäffer, A.A. Faster sequential genetic linkage computations. Am. J. Hum. Genet. 53, 252–263 (1993).

    PubMed  PubMed Central  Google Scholar 

  19. Lathrop, G.M., Lalouel, J.-M., Julier, C. & Ott, J. Strategies for multilocus analysis in humans. Proc. Natl Acad. Sci. USA 81, 3443–3446 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Schäffer, A.A., Gupta, S.K., Shriram, K. & Cottingham, R.W. Jr. Avoiding recomputation in linkage analysis. Hum. Hered. 44, 225–237 (1994).

    Article  PubMed  Google Scholar 

  21. Becker, A., Geiger, D. & Schäffer, A.A. Automatic selection of loop breakers for genetic linkage analysis. Hum. Hered. 48, 49–60 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Broman, K.W., Murray, J.C., Sheffield, V.C., White, R.L. & Weber, J.L. Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am. J. Hum. Genet. 63, 861–869 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Vollrath, D. in Genome Analysis: A Laboratory Manual, Vol. 4 (eds Birren, B. et al.) 187–216 (Cold Spring Harbor Press, Cold Spring Harbor, NY, 1999).

    Google Scholar 

  24. Ho, S.N., Hunt, H.D., Horton, R.M., Pullen, J.K. & Pease, L.R. Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene 77, 51–59 (1989).

    Article  CAS  PubMed  Google Scholar 

  25. Fiermonte, G., Walker, J.E. & Palmieri, F. Abundant bacterial expression and reconstitution of an intrinsic membrane-transport protein from bovine mitochondria. Biochem. J. 294, 293–299 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Palmieri, F., Indiveri, C., Bisaccia, F. & Iacobazzi, V. Mitochondrial metabolite carrier proteins: purification, reconstitution, and transport studies. Methods Enzymol. 260, 349–369 (1995).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M. Anderson, V. Braden, B. Dacany, A. Dutra, C. Francomano, E. Gutter, S.-Q. Lee-Lin, C. Neeley, L. Rizack, R. Smoker, K. Strauss and V. Timmerman for human subject support, clinical work, physical mapping resources, advice and encouragement. This study used the high-performance computational capabilities of the SGI Origin 2000 system at the Center for Information Technology, Bethesda, Maryland, and was supported by grants from Ministerio dell'Istruzione, dell'Universitá e della Ricerca, Centro di Eccellenza di Genomica comparata, University of Bari and Telethon-Italy, and by intramural research funds of the National Human Genome Research Institute.

Author information

Authors and Affiliations

  1. National Human Genome Research Institute, National Institutes of Health, 49 Convent Drive, Bethesda, 20892-4472, Maryland, USA

    Marjorie J. Rosenberg, Joie Davis, Izabela Makalowska & Leslie G. Biesecker

  2. National Center for Biotechnology Information, National Institutes of Health, Bethesda, Maryland, USA

    Richa Agarwala & Alejandro A. Schäffer

  3. NIH Intramural Sequencing Center, National Institutes of Health, Gaithersburg, Maryland, USA

    Gerard Bouffard

  4. Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, Bari, Italy

    Giuseppe Fiermonte & Ferdinando Palmieri

  5. Logicon R.O.W. Sciences Corporation, Rockville, Maryland, USA

    Mark S. Hilliard

  6. Konrad-Zuse-Zentrum für Informationstechnik, Berlin, Germany

    Thorsten Koch

  7. Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA

    Linda M. Kalikin & Elizabeth M. Petty

  8. The Clinic for Special Children, Strasburg, Pennsylvania, USA

    D. Holmes Morton & Richard I. Kelley

  9. Marshfield Medical Research Foundation, Marshfield, Wisconsin, USA

    James L. Weber

  10. Kennedy-Krieger Institute and Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland, USA

    Richard I. Kelley

Authors
  1. Marjorie J. Rosenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richa Agarwala
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gerard Bouffard
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joie Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Giuseppe Fiermonte
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mark S. Hilliard
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Thorsten Koch
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Linda M. Kalikin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Izabela Makalowska
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. D. Holmes Morton
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Elizabeth M. Petty
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. James L. Weber
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ferdinando Palmieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Richard I. Kelley
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Alejandro A. Schäffer
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Leslie G. Biesecker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marjorie J. Rosenberg.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rosenberg, M., Agarwala, R., Bouffard, G. et al. Mutant deoxynucleotide carrier is associated with congenital microcephaly. Nat Genet 32, 175–179 (2002). https://doi.org/10.1038/ng948

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng948

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing