Mutant deoxynucleotide carrier is associated with congenital microcephaly

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In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
00:06

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila

Published on: August 20, 2019

Marjorie J Rosenberg1, Richa Agarwala, Gerard Bouffard

  • 1National Human Genome Research Institute, National Institutes of Health, 49 Convent Drive, Bethesda, Maryland 20892-4472, USA. marjr@nhgri.nih.gov

Nature Genetics
|August 20, 2002
PubMed

Insights

Amish microcephaly (MCPHA) is a severe genetic disorder linked to a mutation in the SLC25A19 gene. This mutation disrupts mitochondrial deoxynucleotide transport, crucial for prenatal brain development.

Area of Science:

  • Genetics
  • Mitochondrial Biology
  • Human Disease

Background:

  • Amish microcephaly (MCPHA) is a rare autosomal recessive disorder.
  • Characterized by severe congenital microcephaly, elevated urinary alpha-ketoglutarate, and premature death.
  • Observed exclusively in Old Order Amish populations with ancestral ties to Lancaster County, Pennsylvania.

Purpose of the Study:

  • To identify the genetic cause of Amish microcephaly (MCPHA).
  • To investigate the molecular mechanism underlying the disorder.
  • To understand the role of mitochondrial deoxynucleotide transport in prenatal brain development.

Main Methods:

  • Utilized a genealogy database and automated pedigree software to trace family lineages.
  • Conducted a whole-genome scan, fine mapping, and haplotype analysis to localize the disease gene.
  • Performed gene sequencing and functional analysis of the identified gene and its protein product.

Main Results:

  • Identified a single ancestral couple connecting 23 affected nuclear families.
  • Localized the MCPHA-associated gene to a 2 Mb region on chromosome 17q25.
  • Discovered a disease-segregating substitution in the SLC25A19 gene, encoding the mitochondrial deoxynucleotide carrier (DNC).
  • Demonstrated that the mutant DNC protein exhibits impaired transport activity.

Conclusions:

  • A mutation in SLC25A19, causing a loss of DNC transport function, is the cause of MCPHA.
  • Failed deoxynucleotide transport across the inner mitochondrial membrane leads to the disorder.
  • Mitochondrial deoxynucleotide transport is essential for normal prenatal brain growth.

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