Vella 2019 MiPschool Coimbra

From Bioblast
Jump to: navigation, search
Joanna Vella
Genetic variants in mitochondrial respiratory chain complex deficiencies.

Link: MitoEAGLE

Vella J, Laurie S, Matalonga L, Borg J, Soler D, Said E, Felice A (2019)

Event: MiPschool Coimbra 2019


Mitochondrial disorders are considered are genetically heterogenous. The oxidative phosphorylation (OXPHOS) system consists of four multi-protein enzyme complexes CI, CII, CIII, CIV and ATP synthase [1]. We report here two cases of patients suspected to have a mitochondrial disorder whose samples were banked at the University of Malta’s biobank (UM biobank) [2].

The analysis was part of a collaborative BBMRI-Large Prospective Cohort (BBMRI-LPC) project focused on mitochondrial disorders. The full mitochondrial genome sequenicng, whole exome sequencing (WES) and data processing were carried out at Centro Nacional de Análisis Genómico (CNAG-CRG). Phenotypic data was recorded in the RD-Connect PhenoTips instance, and variant filtration and prioritisation was undertaken using the RD-Connect Genome-Phenome Analysis Platform [3].

Patient A (Pt A) inherited nuclear genetic variants in 4 of the 7 ‘core’ membrane embedded CI subunits it encodes: NDUFS1 (N module); NDUFA10 (in ND2); NDUFB9 (in ND5), and a rare homozygous mis-sense variant c.308C>T (rs749249430) in NDUFAF3, a CI assembly factor (Q module). Pt A is also a carrier for TIMM13 and CLPX (Table 1, Figure 1).

Patient B inherited a mt DNA missense mutation in MT-ATP6 c.163A>G at m.8689 and 3 X-linked splicing variants: c.207+2T>G (rs782792601); c.206A>G (rs781909386); and c.205A>G (rs782503581) in NDUFB11 (in ND4) (Table 1, Figure 1).

Mutations in encoding subunits and assembly factors of CI cause mt CI deficiency and mitochondrial disease. A novel variant in ATP6 (m.8689) is associated with mt complex V deficiency and Leigh syndrome. It is thought that multiple mutations on different loci could be responsible for complex phenotypes. A cell line model is being used to study the molecular mechanisms involved in CI and ATP synthase assembly.

WES followed by functional validation of disease alleles could identify disease-causative variants in mitochondrial respiratory chain complexes.

Bioblast editor: Plangger M

Labels: MiParea: mtDNA;mt-genetics, nDNA;cell genetics, Patients 

Stress:Mitochondrial disease 

Enzyme: Complex I 

Affiliations and support

Vella J(1), Laurie S(2), Matalonga L(2), Borg J(1,3), Soler D(4), Said E(4), Felice A(1,3,4)
  1. Centre Molecular Medicine Biobanking, Univ Malta, Msida, Malta,
  2. Centro Nacional Análisis Genómico (CNAG-CRG), Center Genomic Regulation, Barcelona Inst Science Technology (BIST), Univ Pompeu Fabra (UPF), Barcelona, Spain
  3. Dept Applied Biomedical Science, Physiology Biochemistry, Univ Malta, Msida
  4. Dept Paediatrics Pathology, Mater Dei Hospital; Malta.
The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 2012-305444, the 2016 BBMRI-LPC WES call and the Malta Government Scholarship Scheme.

Figures and Tables

Vella Table1.jpg

Table 1: Candidate variants from WES.

Vella Figure1.jpg

Figure 1: (left) modular composition of mt CI; (right) Assembly pathway of mt CI4.


  1. Gnaiger E, Aasander Frostner E, Abdul Karim N, Abumrad NA, Acuna-Castroviejo D, Adiele RC, et al (2019) Mitochondrial respiratory states and rates. MitoFit Preprint Arch doi:10.26124/mitofit:190001.v4.
  4. Formosa LE, Dibley MG, Stroud DA, Ryan MT (2018) Building a complex complex: assembly of mitochondrial respiratory chain complex I. Semin Cell Dev Biol 76:154-62.