Infantile Encephaloneuromyopathy and Defective Mitochondrial Translation Are Due to a Homozygous RMND1 Mutation

Defects of mitochondrial protein synthesis are clinically and genetically heterogeneous. We previously described a male infant who was born to consanguineous parents and who presented with severe congenital encephalopathy, peripheral neuropathy, myopathy, and lactic acidosis associated with deficiencies of multiple mitochondrial respiratory-chain enzymes and defective mitochondrial translation. In this work, we have characterized four additional affected family members, performed homozygosity mapping, and identified a homozygous splicing mutation in the splice donor site of exon 2 (c.504+1G>A) of RMND1 (required for meiotic nuclear division-1) in the affected individuals. Fibroblasts from affected individuals expressed two aberrant transcripts and had decreased wild-type mRNA and deficiencies of mitochondrial respiratory-chain enzymes. The RMND1 mutation caused haploinsufficiency that was rescued by overexpression of the wild-type transcript in mutant fibroblasts; this overexpression increased the levels and activities of mitochondrial respiratory-chain proteins. Knockdown of RMND1 via shRNA recapitulated the biochemical defect of the mutant fibroblasts, further supporting a loss-of-function pathomechanism in this disease. RMND1 belongs to the sif2 family, an evolutionary conserved group of proteins that share the DUF155 domain, have unknown function, and have never been associated with human disease. We documented that the protein localizes to mitochondria in mammalian and yeast cells. Further studies are necessary for understanding the function of this protein in mitochondrial protein translation.

Time lags of the kilohertz quasi-periodic oscillations in the low-mass X-ray binaries 4U 1608−52 and 4U 1636−53

We studied the energy and frequency dependence of the Fourier time lags and intrinsic coherence of the kilohertz quasi-periodic oscillations (kHz QPOs) in the neutron-star lowmass X-ray binaries 4U 1608−52 and 4U 1636−53, using a large data set obtained with the Rossi X-ray Timing Explorer. We confirmed that, in both sources, the time lags of the lower kHz QPO are soft and their magnitude increases with energy. We also found that: (i) In 4U 1636−53, the soft lags of the lower kHz QPO remain constant at∼30 μs in the QPO frequency range 500–850 Hz, and decrease to ∼10 μs when the QPO frequency increases further. In 4U 1608−52, the soft lags of the lower kHz QPO remain constant at 40 μs up to 800 Hz, the highest frequency reached by this QPO in our data. (ii) In both sources, the time lags of the upper kHz QPO are hard, independent of energy or frequency and inconsistent with the soft lags of the lower kHz QPO. (iii) In both sources the intrinsic coherence of the lower kHz QPO remains constant at ∼0.6 between 5 and 12 keV, and drops to zero above that energy. The intrinsic coherence of the upper kHz QPO is consistent with being zero across the full energy range. (iv) In 4U 1636−53, the intrinsic coherence of the lower kHz QPO increases from ∼0 at ∼600 Hz to ∼1, and it decreases to ∼0.5 at 920 Hz; in 4U 1608−52, the intrinsic coherence is consistent with the same trend. (v) In both sources the intrinsic coherence of the upper kHz QPO is consistent with zero over the full frequency range of the QPO, except in 4U 1636−53 between 700 and 900 Hz where the intrinsic coherence marginally increases. We discuss our results in the context of scenarios in which the soft lags are either due to reflection off the accretion disc or up-/down-scattering in a hot medium close to the neutron star. We finally explore the connection between, on one hand the time lags and the intrinsic coherence of the kHz QPOs, and on the other the QPOs’ amplitude and quality factor in these two sources.