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