RGD Reference Report - Mutant deoxynucleotide carrier is associated with congenital microcephaly. - Rat Genome Database

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Mutant deoxynucleotide carrier is associated with congenital microcephaly.

Authors: Rosenberg, MJ  Agarwala, R  Bouffard, G  Davis, J  Fiermonte, G  Hilliard, MS  Koch, T  Kalikin, LM  Makalowska, I  Morton, DH  Petty, EM  Weber, JL  Palmieri, F  Kelley, RI  Schaffer, AA  Biesecker, LG 
Citation: Rosenberg MJ, etal., Nat Genet. 2002 Sep;32(1):175-9. Epub 2002 Aug 19.
RGD ID: 1624242
Pubmed: PMID:12185364   (View Abstract at PubMed)
DOI: DOI:10.1038/ng948   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
microcephaly  IAGP 1624242Microcephaly more ...RGD 
microcephaly  ISOSLC25A19 (Homo sapiens)1624242; 1624242Microcephaly more ...RGD 

Objects Annotated

Genes (Rattus norvegicus)
Slc25a19  (solute carrier family 25 member 19)

Genes (Mus musculus)
Slc25a19  (solute carrier family 25 (mitochondrial thiamine pyrophosphate carrier), member 19)

Genes (Homo sapiens)
SLC25A19  (solute carrier family 25 member 19)


Additional Information