Mitochondrial diseases are defined by a respiratory chain dysfunction and in most of the cases manifest as multisystem disorders with predominant expression in muscles and nerves and may be caused by mutations in mitochondrial (mtDNA) or nuclear (nDNA) genomes. Most of the proteins involved in respiratory chain function are nuclear encoded, although 13 subunits of respiratory chain complexes (together with 2 rRNAs and 22 tRNAs necessary for their translation) encoded by mtDNA are essential for cell function. nDNA encodes not only respiratory chain subunits but also all the proteins responsible for mtDNA maintenance, especially those involved in replication, as well as other proteins necessary for the transcription and copy number control of this multicopy genome. Mutations in these genes can cause secondary instability of the mitochondrial genome in the form of depletion (decreased number of mtDNA molecules in the cell), vast multiple deletions or accumulation of point mutations which in turn leads to mitochondrial diseases inherited in a Mendelian fashion. The list of genes involved in mitochondrial DNA maintenance is long, and still incomplete.

RNase H1 is able to recognize DNA/RNA heteroduplexes and to degrade their RNA component. As a consequence, it has been implicated in different aspects of mtDNA replication such as primer formation, primer removal, and replication termination, and significant differences have been reported between control and mutant RNASEH1 skin fibroblasts from patients. However, neither mtDNA depletion nor the presence of deletions have been described in skin fibroblasts while still presenting signs of mitochondrial dysfunction (lower mitochondrial membrane potential, reduced oxygen consumption, slow growth in galactose). Here, we show that RNase H1 has an effect on mtDNA transcripts, most likely through the regulation of 7S RNA and other R-loops. The observed effect on both mitochondrial mRNAs and 16S rRNA results in decreased mitochondrial translation and subsequently mitochondrial dysfunction in cells carrying mutations in RNASEH1.

The classification of mucopolysaccharidoses (MPSs) includes the classical types (I; II; III with subtypes A, B, C, and D; IV with subtypes A and B; VI; VII; IX; X), associated with impaired lysosomal degradation of mucopolysaccharides, also known as glycosaminoglycans (GAGs), as a result of deficiency in the specific enzymes responsible for GAG degradation (MPS IIIE has so far been identified only in animal models) and MPS-plus syndrome (MPSPS), which is characterized by an accumulation of undegraded GAGs, arising from impaired endosomal trafficking and inefficient delivery of these compounds to lysosomes (due to the VPS33A protein deficiency with normal GAG-degrading enzyme activities assessed in vitro). The aim of this comprehensive review is to provide physicians with a clinical, biochemical, and molecular overview of MPS manifestation. A brief summary of available and emerging therapies is also presented.

Introduction: A lack of experience diagnosing and treating rare diseases contributes to delayed or incorrect diagnoses, and optimal clinical treatment is often unachievable. Miller-McKusick-Malvaux syndrome (3M syndrome, also known as dolichospondylic dysplasia) is a rare genetic disorder with unknown prevalence. It is inherited in an autosomal recessive manner and is characterized by severe intrauterine and postnatal growth retardation, dysmorphic facial features, and skeletal abnormalities. Methods: Whole exome sequencing (WES) was performed on the proband using Twist Human Core Exome Plus Kit (Twist Bioscience) and sequenced with Illumina technology (100x depth of mean coverage). Alignment and variant calling were performed with an in-house bioinformatics pipeline. The identified variants were annotated using the Ensembl VEP and multiple databases, including ClinVar, dbSNP, HGMD, and GnomAD. XHMMv1.0. Results: This article presents the diagnostic process in siblings diagnosed with 3M syndrome, caused by homozygous variant c.3523C > T (p.His1175Tyr) in the CUL7 gene. Discussion: This is the first description of a familial syndrome from a local population. Identifying new gene variants has helped expand the spectrum of variations associated with the pathogenesis of 3M syndrome. The expanding database of genetic variants, combined with knowledge of the spectrum and severity of a patient’s clinical symptoms, provides the opportunity to identify genotype-phenotype correlation relevant to medical care.

Choroby mitochondrialne wynikają z nieprawidłowej funkcji mitochondrialnego systemu fosforylacji oksydacyjnej: łańcucha oddechowego i syntazy ATP, produkującego energię komórkową w formie ATP. Jest to zróżnicowana grupa chorób dziedzicznych o szerokim spektrum objawów klinicznych mogących pojawić się w każdym wieku. Mogą one być wynikiem mutacji zarówno w mitochondrialnym DNA, jak i DNA jądrowym. Duża zmienność fenotypu pacjentów utrudnia ich diagnozowanie. Ostatnie osiągnięcia w dziedzinie diagnostyki i badań genetycznych oraz nowe metody reprodukcyjne są ogromną szansą na poprawę diagnostyki, leczenia i ograniczenie chorób mitochondrialnych. W tej pracy przedstawiono nowe zagadnienia pozwalające lepiej zrozumieć etiologię tych chorób oraz postęp w ich diagnozowaniu.

Hereditary myopathy with lactic acidosis due to Iron-Sulfur Cluster Assembly Enzyme (ISCU) deficiency is a rare disorder of energy metabolism characterized clinically by myopathy with exercise intolerance, and biochemically by deficiencies of skeletal muscle mitochondrial respiratory chain enzymes. ISCU protein plays an important role in iron-sulphur clusters (Fe-S) assembly and is therefore essential for the activity of mitochondrial Fe-S proteins such as succinate dehydrogenase and aconitase. Recessive hypomorphic ISCU alleles have been associated with hereditary myopathy with lactic acidosis, also known as Swedish-type myopathy. To date, only one heterozygous dominant variant (c.287G>T, p.Gly96Val) in the ISCU gene has been reported as pathogenic. Functional studies have shown that this variant has a detrimental, dominant effect on activity of Fe-S-dependent enzymes. Whole exome sequencing performed in an adult female patient with progressive muscle weakness led to the identification of a novel heterozygous variant c.399del (p.Val134Ter) in the ISCU gene. This variant is localized in the functional IscU_like domain of the ISCU protein, with bioinformatics prediction of damaging effects on protein function. Moreover, the same variant was also found in a few family members, who present signs of myopathy. This novel variant segregates with the disease and results in a phenotype reminiscent of the recessive disease previously reported. Yeast Saccharomyces cerevisiae is a widely used tool able to assess the impact of the VUS in a quick and efficient way, therefore functional studies were performed on this model system. The results obtained not only confirm the pathogenetic effect of the variant, but also support its dominant inheritance.