Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Oct 5;101(4):525-538.
doi: 10.1016/j.ajhg.2017.08.015. Epub 2017 Sep 21.

Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies

René G Feichtinger  1 , Monika Oláhová  2 , Yoshihito Kishita  3 , Caterina Garone  4 , Laura S Kremer  5 , Mikako Yagi  6 , Takeshi Uchiumi  6 , Alexis A Jourdain  7 , Kyle Thompson  2 , Aaron R D'Souza  8 , Robert Kopajtich  9 , Charlotte L Alston  2 , Johannes Koch  1 , Wolfgang Sperl  1 , Elisa Mastantuono  5 , Tim M Strom  5 , Saskia B Wortmann  10 , Thomas Meitinger  11 , Germaine Pierre  12 , Patrick F Chinnery  8 , Zofia M Chrzanowska-Lightowlers  2 , Robert N Lightowlers  2 , Salvatore DiMauro  13 , Sarah E Calvo  7 , Vamsi K Mootha  7 , Maurizio Moggio  14 , Monica Sciacco  14 , Giacomo P Comi  15 , Dario Ronchi  15 , Kei Murayama  16 , Akira Ohtake  17 , Pedro Rebelo-Guiomar  18 , Masakazu Kohda  3 , Dongchon Kang  6 , Johannes A Mayr  1 , Robert W Taylor  2 , Yasushi Okazaki  3 , Michal Minczuk  8 , Holger Prokisch  19
Affiliations

Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies

René G Feichtinger et al. Am J Hum Genet. .

Abstract

Complement component 1 Q subcomponent-binding protein (C1QBP; also known as p32) is a multi-compartmental protein whose precise function remains unknown. It is an evolutionary conserved multifunctional protein localized primarily in the mitochondrial matrix and has roles in inflammation and infection processes, mitochondrial ribosome biogenesis, and regulation of apoptosis and nuclear transcription. It has an N-terminal mitochondrial targeting peptide that is proteolytically processed after import into the mitochondrial matrix, where it forms a homotrimeric complex organized in a doughnut-shaped structure. Although C1QBP has been reported to exert pleiotropic effects on many cellular processes, we report here four individuals from unrelated families where biallelic mutations in C1QBP cause a defect in mitochondrial energy metabolism. Infants presented with cardiomyopathy accompanied by multisystemic involvement (liver, kidney, and brain), and children and adults presented with myopathy and progressive external ophthalmoplegia. Multiple mitochondrial respiratory-chain defects, associated with the accumulation of multiple deletions of mitochondrial DNA in the later-onset myopathic cases, were identified in all affected individuals. Steady-state C1QBP levels were decreased in all individuals' samples, leading to combined respiratory-chain enzyme deficiency of complexes I, III, and IV. C1qbp-/- mouse embryonic fibroblasts (MEFs) resembled the human disease phenotype by showing multiple defects in oxidative phosphorylation (OXPHOS). Complementation with wild-type, but not mutagenized, C1qbp restored OXPHOS protein levels and mitochondrial enzyme activities in C1qbp-/- MEFs. C1QBP deficiency represents an important mitochondrial disorder associated with a clinical spectrum ranging from infantile lactic acidosis to childhood (cardio)myopathy and late-onset progressive external ophthalmoplegia.

Keywords: MAM33; PEO; lactate; mitochondria; multiple mtDNA deletions; myopathy; oxidative phosphorylation; p32; progressive external ophthalmoplegia.

PubMed Disclaimer

Figures

Figure 1
Figure 1
C1QBP Variants and Gene and Protein Structure (A) Pedigrees of the investigated families (S1–S4) affected by recessively inherited C1QBP variants. Affected individuals are indicated by closed symbols. Both variants in proband S2 have been confirmed to be compound heterozygous by phasing of WES data. (B) Gene structure with exons and introns shows the localization of the investigated gene variations. Conservation of the affected amino acid residues is presented in the alignment of homologs across different species. Exons are highlighted in blue. The size of the introns was reduced 10-fold. MTS is the mitochondrial target sequence. MAM33 (mitochondrial acidic matrix protein 33) is the Saccharomyces cerevisiae homolog of C1QBP. (C) Inspection of the protein structure was performed with PyMOL (PDB: 1P32). A monomer is presented on the left, and the trimer is in the center. The electrostatic field of the trimer is indicated to the right (negative polarity, red; positive polarity, blue). Affected residues are colored in one of the monomers: Cys186, green; Tyr188, blue; Phe204, red; Gly247, magenta; and Leu275, orange.
Figure 2
Figure 2
Western Blot Analysis of C1QBP Cell lysates isolated from (A) the skeletal muscle of affected probands S1, S3, and S4 and (B) fibroblasts from probands S1–S3 and age-matched control individuals (C1 and C2) were analyzed. Fibroblasts from proband S4 and skeletal muscle from proband S2 were not available. β-actin and α-tubulin were used as loading controls. All experiments were repeated at least two times, and representative images are shown. Number of repeats: (A) n = 3 (S1) and n = 2 (S3 and S4); (B) n = 2 (S1–S3).
Figure 3
Figure 3
Steady-State Levels of OXPHOS Complex Subunits (A) Western blot analysis of OXPHOS subunits in skeletal-muscle lysates from control individuals (C1 and C2) and probands S1, S3, and S4. (B) Western blot analysis of OXPHOS subunits in skin fibroblasts from probands S1–S3 and age-matched control individuals (C1–C3). OXPHOS-subunit-specific antibodies were used against NDUFB8 or NDUFA9 (CI); SDHA or SDHB (CII); UQCRC2 (CIII); COXI, COXII, or COXIV (CIV); and ATP5A (CV). Cytosolic β-actin and mitochondrial markers porin (VDAC) and SDHA were used as loading controls. All experiments were repeated at least twice, and representative western blots are shown. Number of repeats: (A) n = 3 (S1) and n = 2 (S3 and S4); (B) n = 4 (S1) and n = 2 (S2 and S3).
Figure 4
Figure 4
BN-PAGE of OXPHOS Complexes One-dimensional BN-PAGE analysis of OXPHOS complexes was performed on mitochondrial lysates isolated from probands’ (A) skeletal muscle (S1 and S3) and (B) fibroblasts (S1–S3) and age-matched control individuals (C1 and C2). The assembly of OXPHOS complexes was assessed by western blotting with antibodies against NDUFB8 (CI), SDHA (CII), UQCRC2 (CIII), COXI (CIV), and ATP5A (CV). An antibody against complex II subunit SDHA was used as a loading control. The ATP5A antibody detected two bands: the fully assembled complex V (F0F1) and the soluble F1 subunit. The asterisk indicates a longer exposure time for the CV F1 subunit. All experiments were repeated at least twice, and representative images are shown. Number of repeats: (A) n = 4 (S1) and n = 2 (S3); (B) n = 4 (S1) and n = 2 (S2 and S3).
Figure 5
Figure 5
Complementation Studies Using C1qbp−/− Mouse Fibroblasts (A) Quantification of C1QBP, COXI, and COXIII levels. Top: WT or C1qbp KO MEFs were transfected with the pcDNA3-C1qbp-IRES-GFP plasmid for 48 hr. Western blotting on total cell extracts was performed with anti-C1QBP, anti-COXI, anti-COXIII, anti-GFP, and anti-VDAC antibodies. VDAC was used as the loading control. Bottom: the mean ratios of band densities in transfected MEFs from blots are shown. Cells transfected with expression constructs for p.Gly244Trp and p.Leu272Pro variants show significantly lower amounts of mature C1QBP and mitochondrial-DNA-encoded proteins (COXI and COXIII). The results represent the mean ± SD of three independent experiments. ∗∗∗p < 0.005 versus WT transfectant. (B) Relative mRNA expression of C1qbp alleles normalized to mouse 18S rRNA by quantitative real-time PCR. The results represent the mean ± SD of three independent experiments. (C and D) Oxygen consumption rate (OCR) profile (C) and histogram of C1qbp KO cells transfected with WT and mutant C1qbp plasmid (D). The histogram shows the basal respiration rate (basal), ATP production rate (ATP), and maximal respiration rate (maximal) calculated from OCR profiles. Data show the mean ± SD of triplicated assays. ∗∗p < 0.01 and ∗∗∗p < 0.005 versus WT transfectant.
Figure 6
Figure 6
Long-Range PCR and Southern Blot of Individuals with Multiple mtDNA Deletions and Control Individuals (A) Long-range PCR of S3. (B) Southern blot of proband S4. mtDNA was amplified with two primer pairs, giving 16,147 bp (F1) and 15,679 (F2) bp fragments. 5 μL of the amplified mtDNA was loaded onto a 0.7% agarose gel and separated at 80 V for 1 hr. Abbreviations are as follows: S3M, muscle of proband S3; S3F, fibroblasts of proband S3; S4, muscle of proband S4; M, marker λ/HindIII; C1–C3: control cells.
See this image and copyright information in PMC

Similar articles

  • Single Large-Scale Mitochondrial DNA Deletion Syndromes.
    Goldstein A, Falk MJ. Goldstein A, et al. 2003 Dec 17 [updated 2023 Sep 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. 2003 Dec 17 [updated 2023 Sep 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. PMID: 20301382 Free Books & Documents. Review.
  • Genetics, X-Linked Inheritance.
    Basta M, Pandya AM. Basta M, et al. 2023 May 1. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan–. 2023 May 1. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan–. PMID: 32491315 Free Books & Documents.
  • EMS Diabetic Protocols For Treat and Release.
    Schwerin DL, Svancarek B. Schwerin DL, et al. 2023 Jul 17. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan–. 2023 Jul 17. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan–. PMID: 32809447 Free Books & Documents.
  • Bi-allelic variants in DAP3 result in reduced assembly of the mitoribosomal small subunit with altered apoptosis and a Perrault-syndrome-spectrum phenotype.
    Smith TB, Kopajtich R, Demain LAM, Rea A, Thomas HB, Schiff M, Beetz C, Joss S, Conway GS, Shukla A, Yeole M, Radhakrishnan P, Azzouz H, Ben Chehida A, Elmaleh-Bergès M, Glasgow RIC, Thompson K, Oláhová M, He L, Jenkinson EM, Jahic A, Belyantseva IA, Barzik M, Urquhart JE, O'Sullivan J, Williams SG, Bhaskar SS, Carrera S, Blakes AJM, Banka S, Yue WW, Ellingford JM, Houlden H; DDD Study; Munro KJ, Friedman TB, Taylor RW, Prokisch H, O'Keefe RT, Newman WG. Smith TB, et al. Am J Hum Genet. 2025 Jan 2;112(1):59-74. doi: 10.1016/j.ajhg.2024.11.007. Epub 2024 Dec 18. Am J Hum Genet. 2025. PMID: 39701103 Free PMC article.
  • Adenosine Deaminase Deficiency.
    Hershfield M, Tarrant T. Hershfield M, et al. 2006 Oct 3 [updated 2024 Mar 7]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. 2006 Oct 3 [updated 2024 Mar 7]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. PMID: 20301656 Free Books & Documents. Review.
See all similar articles

Cited by

See all "Cited by" articles

References

    1. Mayr J.A., Haack T.B., Freisinger P., Karall D., Makowski C., Koch J., Feichtinger R.G., Zimmermann F.A., Rolinski B., Ahting U. Spectrum of combined respiratory chain defects. J. Inherit. Metab. Dis. 2015;38:629–640. - PMC - PubMed
    1. Mayr J.A. Disorders of Oxidative Phosphorylation. In: Saudubray J.M., editor. Inborn Metabolic Diseases. Springer; 2016. pp. 223–242.
    1. Craven L., Alston C.L., Taylor R.W., Turnbull D.M. Recent Advances in Mitochondrial Disease. Annu. Rev. Genomics Hum. Genet. 2017;18:257–275. - PubMed
    1. Kohda M., Tokuzawa Y., Kishita Y., Nyuzuki H., Moriyama Y., Mizuno Y., Hirata T., Yatsuka Y., Yamashita-Sugahara Y., Nakachi Y. A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies. PLoS Genet. 2016;12:e1005679. - PMC - PubMed
    1. Kremer L.S., L’hermitte-Stead C., Lesimple P., Gilleron M., Filaut S., Jardel C., Haack T.B., Strom T.M., Meitinger T., Azzouz H. Severe respiratory complex III defect prevents liver adaptation to prolonged fasting. J. Hepatol. 2016;65:377–385. - PMC - PubMed

MeSH terms