Mutant deoxynucleotide carrier is associated with congenital microcephaly

Nat Genet. 2002 Sep;32(1):175-9. doi: 10.1038/ng948. Epub 2002 Aug 19.

Abstract

The disorder Amish microcephaly (MCPHA) is characterized by severe congenital microcephaly, elevated levels of alpha-ketoglutarate in the urine and premature death. 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), 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Christianity
  • Chromosomes, Human, Pair 17
  • Cloning, Molecular
  • Deoxyribonucleotides / metabolism*
  • Escherichia coli
  • Ethnic Groups
  • Female
  • Genetic Markers
  • Haplotypes
  • Humans
  • Lod Score
  • Male
  • Membrane Transport Proteins*
  • Microcephaly / genetics*
  • Mutation
  • Pedigree
  • Physical Chromosome Mapping
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism

Substances

  • Carrier Proteins
  • Deoxyribonucleotides
  • Genetic Markers
  • Membrane Transport Proteins
  • Recombinant Proteins
  • SLC25A19 protein, human