Mutant deoxynucleotide carrier is associated with congenital microcephaly.
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.
Rosenberg
Marjorie J
MJ
National Human Genome Research Institute, National Institutes of Health, 49 Convent Drive, Bethesda, Maryland 20892-4472, USA. marjr@nhgri.nih.gov
Agarwala
Richa
R
Bouffard
Gerard
G
Davis
Joie
J
Fiermonte
Giuseppe
G
Hilliard
Mark S
MS
Koch
Thorsten
T
Kalikin
Linda M
LM
Makalowska
Izabela
I
Morton
D Holmes
DH
Petty
Elizabeth M
EM
Weber
James L
JL
Palmieri
Ferdinando
F
Kelley
Richard I
RI
Schäffer
Alejandro A
AA
Biesecker
Leslie G
LG
D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002835:Christianity; D002886:Chromosomes, Human, Pair 17; D003001:Cloning, Molecular; D003854:Deoxyribonucleotides / Q000378:metabolism*; D004926:Escherichia coli; D005006:Ethnicity; D005260:Female; D005819:Genetic Markers; D006239:Haplotypes; D006801:Humans; D008126:Lod Score; D008297:Male; D026901:Membrane Transport Proteins; D008831:Microcephaly / Q000235:genetics*; D033681:Mitochondrial Membrane Transport Proteins; D009154:Mutation; D010375:Pedigree; D020161:Physical Chromosome Mapping; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D002352:Carrier Proteins; D003854:Deoxyribonucleotides; D005819:Genetic Markers; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D011994:Recombinant Proteins; C434255:SLC25A19 protein, human