Nature Genetics
32, 175 - 179 (2002)
Published online: 19 August 2002; | doi:10.1038/ng948
Mutant deoxynucleotide carrier is associated with congenital microcephalyMarjorie J. Rosenberg1, Richa Agarwala2, Gerard Bouffard3, Joie Davis1, Giuseppe Fiermonte4, Mark S. Hilliard5, Thorsten Koch6, Linda M. Kalikin7, Izabela Makalowska1, D. Holmes Morton8, Elizabeth M. Petty7, James L. Weber9, Ferdinando Palmieri4, Richard I. Kelley8, 10, Alejandro A. Schäffer2
& Leslie G. Biesecker11
National Human Genome Research Institute, National Institutes of Health, 49 Convent Drive, Bethesda, Maryland 20892-4472, USA. 2
National Center for Biotechnology Information, National Institutes of Health, Bethesda, Maryland, USA. 3
NIH Intramural Sequencing Center, National Institutes of Health, Gaithersburg, Maryland, USA. 4
Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, Bari, Italy. 5
Logicon R.O.W. Sciences Corporation, Rockville, Maryland, USA. 6
Konrad-Zuse-Zentrum für Informationstechnik, Berlin, Germany. 7
University of Michigan Medical Center, Department of Internal Medicine, Ann Arbor, Michigan, USA. 8
The Clinic for Special Children, Strasburg, Pennsylvania, USA. 9
Marshfield Medical Research Foundation, Marshfield, Wisconsin, USA. 10
Kennedy-Krieger Institute and Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland, USA.
Correspondence should be addressed to Marjorie J. Rosenberg marjr@nhgri.nih.govThe disorder Amish microcephaly (MCPHA) is characterized by severe congenital microcephaly, elevated levels of  -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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