Mutant deoxynucleotide carrier is associated with congenital microcephaly
| Autor: | Linda M. Kalikin, Richa Agarwala, James L. Weber, Leslie G. Biesecker, D. Holmes Morton, Ferdinando Palmieri, Elizabeth M. Petty, Richard I. Kelley, Joie Davis, Izabela Makalowska, Thorsten Koch, Giuseppe Fiermonte, Marjorie J. Rosenberg, Mark S. Hilliard, Alejandro A. Schäffer, Gerard G. Bouffard |
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| Rok vydání: | 2002 |
| Předmět: |
Genetic Markers
Male Microcephaly Mutant Deoxyribonucleotides Biology Mitochondrial Membrane Transport Proteins Christianity Deoxynucleotide transport Genetics medicine Escherichia coli Ethnicity Humans Cloning Molecular Inner mitochondrial membrane Gene Haplotype Chromosome Membrane Transport Proteins medicine.disease Physical Chromosome Mapping Recombinant Proteins Pedigree Haplotypes Mutation Old Order Amish Female Lod Score Carrier Proteins Chromosomes Human Pair 17 |
| Zdroj: | Nature genetics. 32(1) |
| ISSN: | 1061-4036 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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