Mutation screening in patients with isolated complex I deficiency in the mitochondrial respiratory chain

In dieser Arbeit wurde bei 88 Patienten mit isoliertem Komplex-I-Defekt der mitochondrialen Atmungskette ein Hochdurchsatz-Mutationsscreen etabliert. Alle 45 Strukturuntereinheiten sowie die Assemblierungsfaktoren NDUFAF1, NDUFAF2 und ECSIT wurden mittels hochauflösender Schmelzpunktanalyse (HRMA, High Resolution Melting Analysis) untersucht. Bei zwölf Patienten wurden bekannte pathogene bzw. unbekannte wahrscheinlich pathogene Mutationen identifiziert (14%) und deren genetische Diagnostik damit erfolgreich abgeschlossen. Bei 25 Patienten wurden seltene Varianten unklarer Kausalität (29 %) gefunden. Die molekulargenetische Diagnostik für Patienten mit Komplex-I-Defekt konnte durch Etablierung dieses Mutationsscreens erweitert und verbessert werden.A large-scale mutation screen in 88 patients with isolated complex-I-deficiency of the mitochondrial respiratory chain was performed by high-resolution melting curve analysis (HRMA). All 45 subunits of complex I and the assemblyfactors NDUFAF1, NDUFAF2 and ECSIT were investigated. Known causative and unknown likely-causative mutations were detected in 12 patients. Thus, a molecular diagnosis related to complex I deficiency was established in 14% of patients. In further 25 patients variants of unknown significance (VUS) were found (29 %). Establishing this mutation screen has improved the moleculargenetic diagnostics for complex-I-patients

Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy

The autosomal recessive kidney disease nephronophthisis (NPHP) constitutes the most frequent genetic cause of terminal renal failure in the first 3 decades of life. Ten causative genes (NPHP1–NPHP9 and NPHP11), whose products localize to the primary cilia-centrosome complex, support the unifying concept that cystic kidney diseases are “ciliopathies”. Using genome-wide homozygosity mapping, we report here what we believe to be a new locus (NPHP-like 1 [NPHPL1]) for an NPHP-like nephropathy. In 2 families with an NPHP-like phenotype, we detected homozygous frameshift and splice-site mutations, respectively, in the X-prolyl aminopeptidase 3 (XPNPEP3) gene. In contrast to all known NPHP proteins, XPNPEP3 localizes to mitochondria of renal cells. However, in vivo analyses also revealed a likely cilia-related function; suppression of zebrafish xpnpep3 phenocopied the developmental phenotypes of ciliopathy morphants, and this effect was rescued by human XPNPEP3 that was devoid of a mitochondrial localization signal. Consistent with a role for XPNPEP3 in ciliary function, several ciliary cystogenic proteins were found to be XPNPEP3 substrates, for which resistance to N-terminal proline cleavage resulted in attenuated protein function in vivo in zebrafish. Our data highlight an emerging link between mitochondria and ciliary dysfunction, and suggest that further understanding the enzymatic activity and substrates of XPNPEP3 will illuminate novel cystogenic pathways