Mitochondrial hepato-encephalopathy due to deficiency of QIL1/MIC13 (C19orf70), a MICOS complex subunit

Abstract

The mitochondrial inner membrane possesses distinct subdomains including cristae, which are lamellar structures invaginated into the mitochondrial matrix and contain the respiratory complexes. Generation of inner membrane domains requires the complex interplay between the respiratory complexes, mitochondrial lipids and the recently identified mitochondrial contact site and cristae organizing system (MICOS) complex. Proper organization of the mitochondrial inner membrane has recently been shown to be important for respiratory function in yeast. Here we aimed at a molecular diagnosis in a brother and sister from a consanguineous family who presented with a neurodegenerative disorder accompanied by hyperlactatemia, 3-methylglutaconic aciduria, disturbed hepatocellular function with abnormal cristae morphology in liver and cerebellar and vermis atrophy, which suggest mitochondrial dysfunction. Using homozygosity mapping and exome sequencing the patients were found to be homozygous for the p.(Gly15Glufs*75) variant in the QIL1/MIC13 (C19orf70) gene. QIL1/MIC13 is a constituent of MICOS, a six subunit complex that helps to form and/or stabilize cristae junctions and determine the placement, distribution and number of cristae within mitochondria. In patient fibroblasts both MICOS subunits QIL1/MIC13 and MIC10 were absent whereas MIC60 was present in a comparable abundance to that of the control. We conclude that QIL1/MIC13 deficiency in human, is associated with disassembly of the MICOS complex, with the associated aberration of cristae morphology and mitochondrial respiratory dysfunction. 3-Methylglutaconic aciduria is associated with variants in genes encoding mitochondrial inner membrane organizing determinants, including TAZ, DNAJC19, SERAC1 and QIL1/MIC13.

Figure 1

Family pedigree (filled symbols for affected members) with genotyping of the p.(Gly15Glufs*75) variant (del) in the QIL1/MIC13 gene (a). Brain MRI of patient II-1 (b, c) and patient II-3 (d) at 1 year of age: coronal T2-weighted image (b), sagittal T1-weighted turbo spin-echo image (c) and coronal T1-weighted image (d) disclosing small atrophic cerebellar hemispheres and vermis.

Figure 2

Electron microscopy of liver tissue of patient II-1 at 3 years of age: (a, b) representing images of enlarged mitochondria with abnormal distribution, packed cristae with curvilinear pattern and abnormal microtubular structures. Bar – 1 μm. (c) Normal mitochondria (arrows) in the liver of an infant with cholestasis (PFIC).

Figure 3

(a) QIL1/MIC13 frameshift variant causes loss of QIL1/MIC13 expression and destabilization of the MICOS complex. Representative western blot analysis with the indicated antibodies of whole-cell lysates from control (left) and patient II-3 (right) skin fibroblasts. (b) A schematic representation of the consequence of QIL1/MIC13 deficiency is shown. Left: The holo-MICOS complex, consisting of two subcomplexes (MIC60/MIC19/MIC25 in blue; QIL1/MIC10/MIC26/MIC27 in red), is localized to cristae junctions in normal cells. Right: In the patients, QIL1/MIC13 is truncated and missensed and is unstable and non-functional, represented by QIL1/MIC13*. Loss of QIL1/MIC13 function leads to destabilization of the MIC10/MIC26/MIC27 subcomplex, indicated by dashed lines, while MIC60/MIC19/MIC25 remains intact. Loss of QIL1/MIC13 function causes loss or reduction in cristae junctions and altered cristae morphology. A full color version of this figure is available at the European Journal of Human Genetics journal online.