Mutant deoxynucleotide carrier is associated with congenital microcephaly.

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. Microcephaly is caused by several environmental and genetic factors. It can occur as either part of a syndrome or isolation, and can occur with or without structural malformations of the brain 3 . The disorder is characterized by profound microcephaly, a congenital malformation of the brain and an inborn error of metabolism. At least 61 affected infants have been born in the past 40 years in 23 nuclear families. Affected individuals have head circumferences that are 6 to 12 standard deviations less the population mean and abnormally high concentrations of urinary α -ketoglutarate 1 . We considered that the increased levels of α -ketoglutarate might be the result of a defect in the α -ketoglutarate dehydrogenase complex, which comprises three enzymes: 2-oxoglutarate dehydrogenase (OMIM 203740), dihydrolipoamide succinyltransferase (OMIM 126063) and dihydrolipoamide dehydrogenase (OMIM 246900). We excluded genes encoding those enzymes on the basis of genetic linkage and haplotype analysis (data not shown), and concluded that this disorder must be associated with another genetic locus.