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SLC25A4 Membrane Protein Introduction

Introduction of SLC25A4

ADP/ATP translocase 1, also known as heart/skeletal muscle isoform T1, Adenine nucleotide translocator 1, Solute carrier family 25 member 4, is a protein that in humans is encoded by the SLC25A4 gene. The SLC25 family of transporters is the largest of solute carriers and the human SLC25 genes are distributed uniformly in nearly all chromosomes yet differ widely in their organization and size. SLC25A4 or AAC1 deficiency (OMIM 192600) is due to recessive mutations in the SLC25A4 gene which encodes the heart-/muscle-specific ADP/ATP carrier AAC1 (ANT1). Autosomal dominant PEO (OMIM 609283) is another distinct disease from SLC25A4 deficiency and is caused by heterozygous mutations of the SLC25A4 gene encoding AAC1. The disease is also caused by two other nuclear genes: Twinkle encoding an mtDNA helicase and POLC1 encoding the catalytic subunit of the mtDNA-specific polymerase-γ.

Basic Information of SLC25A4
Protein Name ADP/ATP translocase 1
Gene Name SLC25A4
Aliases ADP, ATP carrier protein 1, ADP, ATP carrier protein, heart/skeletal muscle isoform T1, Adenine nucleotide translocator 1, ANT 1, Solute carrier family 25 member 4, ANT1
Organism Homo sapiens (Human)
UniProt ID P12235
Transmembrane Times 6
Length (aa) 298
Sequence MGDHAWSFLKDFLAGGVAAAVSKTAVAPIERVKLLLQVQHASKQISAEKQYKGIIDCVVRIPKEQGFLSFWRGNLANVIRYFPTQALNFAFKDKYKQLFLGGVDRHKQFWRYFAGNLASGGAAGATSLCFVYPLDFARTRLAADVGKGAAQREFHGLGDCIIKIFKSDGLRGLYQGFNVSVQGIIIYRAAYFGVYDTAKGMLPDPKNVHIFVSWMIAQSVTAVAGLVSYPFDTVRRRMMMQSGRKGADIMYTGTVDCWRKIAKDEGAKAFFKGAWSNVLRGMGGAFVLVLYDEIKKYV

Function of SLC25A4 Membrane Protein

The first recessive mutation found in the SLC25A4 gene which encodes the heart-/muscle-specific ADP/ATP carrier (AAC1), was identified in a 25-year-old male patient. The mutation, an alanine-to-aspartic acid replacement (A123D), involves a highly conserved residue which protrudes into the central cavity of the transporter slightly above the level of the common binding site. This leads to a complete loss of the ability of the protein to transport ADP and ATP in reconstituted liposomes. AAC1 deficiency is characterized by exercise intolerance with easy fatigability and muscle pain since early childhood, progressive hypertrophic cardiomyopathy, mild myopathy with no PEO and lactic acidosis.

A second recessive mutation in the SLC25A4 gene, c.111 + 1G > A, abolishing the invariant GT splice donor site of intron 1 and causing a complete loss of AAC1 expression, has recently been described. The symptomatology of the two above-mentioned patients closely resembles that of the SLC25A4 knock-out mice. As in the mouse model, loss of AAC1 function is compatible with adult life, possibly due to compensation by transport activities of AAC isoforms or another adenine nucleotide MCs (the ATP-Mg/Pi carrier, etc.).

Structure of the SLC25A4 protein. Fig.1 Structure of the SLC25A4 protein.

Application of SLC25A4 Membrane Protein in Literature

  1. Körver-Keularts I.M., et al. Two Novel Mutations in the SLC25A4 Gene in a Patient with Mitochondrial Myopathy. JIMD Rep. 2015, 22: 39-45. PubMed ID: 25732997

    The article reports two novel mutations in the SLC25A4 gene in a patient with mitochondrial myopathy. This case is unique with recessive mutations leading to a complete absence of the SLC25A4 protein.

  2. Thompson K., et al. Recurrent De Novo Dominant Mutations in SLC25A4 Cause Severe Early-Onset Mitochondrial Disease and Loss of Mitochondrial DNA Copy Number. Am J Hum Genet. 2016, 99(4): 860-876. PubMed ID: 27693233

    The article reveals that recombinant AAC1 mutant proteins are severely impaired in ADP/ATP transport, affecting substrate binding and mechanics of the carrier, respectively.

  3. Park K.P., et al. SLC25A4 and C10ORF2 Mutations in Autosomal Dominant Progressive External Ophthalmoplegia. J Clin Neurol. 2011, 7(1): 25-30. PubMed ID: 21519523

    Authors in this group identify two known heterozygous missense mutations in SLC25A4 (p.Asp104Gly) and C10ORF2 (p.Glu479Lys) and further studies are necessary to identify the clear pathogenetic mechanisms.

  4. Biomed Rep., et al. Phenotypic spectrum of SLC25A4 mutations. Biomed Rep. 2018, 9(2): 119-122. PubMed ID: 30013777

    The article summarizes and discusses recent findings regarding the clinical presentation and phenotypic heterogeneity of the SLC25A4 mutations.

  5. Tosserams A., et al. Two new cases of mitochondrial myopathy with exercise intolerance, hyperlactatemia and cardiomyopathy, caused by recessive SLC25A4 mutations. Mitochondrion. 2018, 39: 26-29. PubMed ID: 28823815

    The article reports the clinical, morphological and molecular features of two patients with autosomal recessive SLC25A4 (ANT1) gene mutations.

SLC25A4 Preparation Options

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