Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology

Abstract

Mandibuloacral dysplasia syndromes are mainly due to recessive LMNA or ZMPSTE24 mutations, with cardinal nuclear morphological abnormalities and dysfunction. We report five homozygous null mutations in MTX2, encoding Metaxin-2 (MTX2), an outer mitochondrial membrane protein, in patients presenting with a severe laminopathy-like mandibuloacral dysplasia characterized by growth retardation, bone resorption, arterial calcification, renal glomerulosclerosis and severe hypertension. Loss of MTX2 in patients’ primary fibroblasts leads to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients’ fibroblasts are resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation. Interestingly, secondary nuclear morphological defects are observed in both MTX2-mutant fibroblasts and mtx-2-depleted C. elegans. We thus report the identification of a severe premature aging syndrome revealing an unsuspected link between mitochondrial composition and function and nuclear morphology, establishing a pathophysiological link with premature aging laminopathies and likely explaining common clinical features.

Mutations Involved in Premature-Ageing Syndromes

“…In addition to the two major forms of mandibuloacral dysplasia resulting from either LMNA (MADA) or ZMPSTE mutations (MADB), MAD is also a feature of other SPS resembling features of atypical progeroid laminopathies but originating from mutations of genes involved in other pathways. 39 , 40 These include an autosomal dominant form of MAD termed mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) syndrome and caused by mutations in the POLD1 gene encoding the catalytic subunit of DNA polymerase delta, 39 and a recently identified severe premature ageing syndrome with clinical features resembling HGPS termed MADaM (mandibuloacral dysplasia associated to MTX2 ), resulting from homozygous recessive mutations in the MTX2 gene encoding metaxin-2, an outer mitochondrial membrane protein. 40 …”

“…MADaM (OMIM #619127) has been recently described in seven patients from five families originating from India, Turkey, Algeria, Egypt, and Ecuador, and diagnosed as a severe progeroid form of MAD with clinical features resembling HGPS, including small viscerocranium with mandibular underdevelopment, growth retardation, lipodystrophy, altered skin pigmentation, distal acro-osteolyses, renal focal glomerulosclerosis, and severe cardiovascular disease, but all showing normal cognitive development. 40 Patients were first screened for pathogenic mutations in the LMNA, ZMPSTE24, BANF1 , and POLD1 genes, but none was found. 40 Subsequent NGS approaches in affected members of these families revealed five pathogenic recessive mutations in MTX2 , and particularly a c.2T>A missense mutation (p.Met1Lys) in the first family, a c.544–1G>C base substitution within the splice acceptor site in intron 8 in the second family and a c.208+3_208+6del within the splice donor site in intron 4 in the third family, both leading to altered mRNAs resulting in premature termination codons in the protein (respectively, p.Val182Argfs*3 and p.Ala46Valfs*12), a frame-shift mutation in exon 9 in the fourth family (c.603del; p.Tyr202Ilefs*26), and a homozygous 2-bp deletion in exon 6 (c.294_295delTC) resulting in a nonsense mutation (p.Leu99*) in the fifth family.…”

Chromatin architecture reveals cell type-specific target genes for kidney disease risk variants

“…MTX1 is a mitochondrial outer membrane protein [ 41 ]. Loss of its homolog MTX2 leads to mitochondrial dysfunction [ 42 ]. The mammalian kidney tubule relies on abundant mitochondria to provide the energy required for constant reclamation [ 43 ].…”

Loss of C2orf69 defines a fatal auto-inflammatory mitochondriopathy in Humans and Zebrafish

“…Next, we performed cell fractionation using primary human fibroblasts and obtained a major cytosolic localisation and a minor fraction of endogenous C2ORF69 with the mitochondrial and ER/GOLGI membranes (Figure 3B, lanes 1-3). This result was not changed in fibroblasts that are MTX1/2-deficient, 7 two proteins involved in the translocation of nuclear-encoded proteins into the outer mitochondrial membrane (OMM) (Figure 3B, lanes 1-6). To determine the topology and localisation of mitochondrial-associated C2ORF69, HEK293T mitochondrial extracts were treated with proteinase K in the presence of increasing concentrations of digitonin.…”

“…Primary mitochondrial disorders, such as Leigh syndrome (MIM256000), are caused by mutations in components of the electron transport chain that result in bioenergetic defects 5 . Other inherited mitochondrial defects arise from impairments in lipid metabolism 6 , control of cell death 7 , organellar and protein quality control 8 , fission and fusion, metabolite biogenesis 9 that impact OXPHOS and other cellular processes dependent on mitochondrial integrity. Despite extensive efforts to catalogue the mitochondrial proteome 10 , many uncharacterized proteins remain.…”