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Case Reports
. 2007 Aug;81(2):383-7.
doi: 10.1086/519222. Epub 2007 Jun 4.

Deficiency of the alpha subunit of succinate-coenzyme A ligase causes fatal infantile lactic acidosis with mitochondrial DNA depletion

Elsebet Ostergaard  1 , Ernst Christensen, Elisabeth Kristensen, Bodil Mogensen, Morten Duno, Eric A Shoubridge, Flemming Wibrand
Affiliations
Case Reports

Deficiency of the alpha subunit of succinate-coenzyme A ligase causes fatal infantile lactic acidosis with mitochondrial DNA depletion

Elsebet Ostergaard et al. Am J Hum Genet. 2007 Aug.

Abstract

Fatal infantile lactic acidosis is a severe metabolic disorder characterized by the onset of lactic acidosis within the 1st d of life and early death. We found a combined respiratory-chain enzyme deficiency associated with mitochondrial DNA (mtDNA) depletion in a small consanguineous family with this disorder. To identify the disease-causing gene, we performed single-nucleotide polymorphism homozygosity mapping and found homozygous regions on four chromosomes. DNA sequencing revealed a homozygous 2-bp deletion in SUCLG1, a gene that encodes the alpha subunit of the Krebs-cycle enzyme succinate-coenzyme A ligase (SUCL). The mtDNA depletion is likely explained by decreased mitochondrial nucleoside diphosphate kinase (NDPK) activity resulting from the inability of NDPK to form a complex with SUCL.

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Figures

Figure 1.
Figure 1.
Pedigree of the family of Pakistani origin with fatal infantile lactic acidosis due to SUCLG1 mutations.
Figure 2.
Figure 2.
Histology and analysis of the respiratory chain and SUCLG1. A, BN-PAGE of muscle, liver, and fibroblasts, showing a decreased amount of fully assembled complexes I, III, and IV in muscle and liver in patients 1 and 2 (P1 and P2) with SUCLG1 mutations, compared with controls (C). In addition, a subcomplex from complex III is seen (arrow). B, Enzyme analysis of the respiratory chain related to citrate synthase (CS) shows a deficiency of complexes I, III, and IV in muscle (M) from patient 1 and in liver (L) from patient 2 (gray bars). Values±SDs for controls are shown by black bars. C, Histology of muscle and liver. ATPase staining (pH 9.4) (top) and oil red staining (middle) of muscle showing normal fiber-type distribution and intracellular lipid accumulation (arrow). The tissue fragmentation is a freeze artifact. Hematoxylin and eosin staining (bottom) of liver, showing sinusoidal dilatation (arrow) and microvesicular steatosis. D, Mutation analysis of SUCLG1 showing the homozygous c.113_114delAT mutation in patient 1. E, Analysis of the relative mtDNA copy number by Southern-blot analysis of muscle from patient 2 and liver from patient 1 compared with controls. The mtDNA/nuclear DNA (nDNA) ratio is shown below the bands. F, Immunoblot analysis of fibroblast mitochondria showing a complete absence of SUCLG1 protein in patients 1 and 2 compared with controls. An antibody against PDH E2 was used as a loading control.
Figure 3.
Figure 3.
The Krebs cycle and methylmalonate metabolism. CoASH = coenzyme A. Pi = inorganic phosphate.
See this image and copyright information in PMC

References

Web Resources

    1. GenBank, http://www.ncbi.nlm.nih.gov/Genbank/ (for SUCLG1 [accession number NM_003849])
    1. Mitop2, http://www.mitop2.de
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim (for hepatocerebral mtDNA depletion syndromes, MNGIE, and Alpers syndrome)

References

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