Novel Pathogenic Variant of the Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss.

Autosomal dominant non-syndromic hearing loss (ADNSHL) is a genetically heterogenic condition. The transformation/transcription domain associated protein () gene has been recently associated with ADNSHL, and only four variants of the gene have so far been reported in this disease. Here, we report on a Hungarian ADNSHL family in which the affected individuals exhibited sensorineural hearing loss with similar clinical symptoms, including initial impaired high frequencies that subsequently affected speech and lower frequencies.

Novel and Variants and the Observed Clinical Outcomes in a Hungarian Melanoma Cohort.

Accumulating evidence suggests that inherited melanoma is not rare and approx. one in seven individuals with melanoma has clinically relevant hereditable cancer-predisposing and/or -susceptibility variant(s). Concerning its germline genetic background, genetic screening aims to identify either variants of predisposing genes with high penetrance or variants of susceptibility genes with medium or low penetrance.

Novel Variants in Medium and Low Penetrance Predisposing Genes in a Hungarian Malignant Melanoma Cohort With Increased Risk.

Both germline and somatic variants contribute to the genetic background and pathogenesis of melanoma. Germline variants include the presence of rare pathogenic or likely pathogenic variants of high, medium, and low penetrance melanoma-predisposing genes. Rare variants of high penetrance melanoma-predisposing genes are associated with melanoma development, whereas the medium and low penetrance predisposing genes can significantly increase melanoma risk.

Missing Heritability in Albinism: Deep Characterization of a Hungarian Albinism Cohort Raises the Possibility of the Digenic Genetic Background of the Disease.

Albinism is characterized by a variable degree of hypopigmentation affecting the skin and the hair, and causing ophthalmologic abnormalities. Its oculocutaneous, ocular and syndromic forms follow an autosomal or X-linked recessive mode of inheritance, and 22 disease-causing genes are implicated in their development. Our aim was to clarify the genetic background of a Hungarian albinism cohort.

Beyond C9orf72: repeat expansions and copy number variations as risk factors of amyotrophic lateral sclerosis across various populations.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder which is characterized by the loss of both upper and lower motor neurons in the central nervous system. In a significant fraction of ALS cases - irrespective of family history- a genetic background may be identified. The genetic background of ALS shows a high variability from one ethnicity to another.

A novel de novo truncating variant in a Hungarian patient with CTNNB1 neurodevelopmental disorder.

Purpose: We aimed to elucidate the underlying disease in a Hungarian family, with only one affected family member, a 16-year-old male Hungarian patient, who developed global developmental delay, cognitive impairment, behavioral problems, short stature, intermittent headaches, recurrent dizziness, strabismus, hypermetropia, complex movement disorder and partial pituitary dysfunction. After years of detailed clinical investigations and careful pediatric care, the exact diagnosis of the patient and the cause of the disease was still unknown.

Methods: We aimed to perform whole exome sequencing (WES) in order to investigate whether the affected patient is suffering from a rare monogenic disease.

Whole-Exome Sequencing Identified Two Novel Pathogenic Mutations in the Gene in BCNS.

Basal cell nevus syndrome (BCNS, OMIM 109400) is a familial cancer syndrome characterized by the development of numerous basal cell cancers and various other developmental abnormalities, including epidermal cysts of the skin, calcified dural folds, keratocysts of the jaw, palmar and plantar pits, ovarian fibromas, medulloblastomas, lymphomesenteric cysts, and fetal rhabdomyomas. BCNS shows autosomal dominant inheritance and is caused by mutations in the patched 1 () gene and the suppressor of the fused homolog () gene. In a few cases, variants of patched 2 () have been found in patients who met the criteria for BCNS.

Genetic Etiology of Nonsyndromic Hearing Loss in Hungarian Patients.

Hearing loss is the most prevalent sensory disorder worldwide. The majority of congenital nonsyndromic hearing loss (NSHL) cases are caused by hereditary factors. Previously, the majority of NSHL studies focused on the gene; however, with the availability of next-generation sequencing (NGS) methods, the number of novel variants associated with NSHL has increased.

Likely Pathogenic Variants of Ca1.3 and Na1.1 Encoding Genes in Amyotrophic Lateral Sclerosis Could Elucidate the Dysregulated Pain Pathways.

Amyotrophic lateral sclerosis (ALS) is a lethal multisystem neurodegenerative disease associated with progressive loss of motor neurons, leading to death. Not only is the clinical picture of ALS heterogenous, but also the pain sensation due to different types of pain involvement. ALS used to be considered a painless disease, but research has been emerging and depicting a more complex pain representation in ALS.

STABILON, a Novel Sequence Motif That Enhances the Expression and Accumulation of Intracellular and Secreted Proteins.

The dynamic balance of transcriptional and translational regulation together with degron-controlled proteolysis shapes the ever-changing cellular proteome. While a large variety of degradation signals has been characterized, our knowledge of -acting protein motifs that can in vivo stabilize otherwise short-lived proteins is very limited. We have identified and characterized a conserved 13-mer protein segment derived from the p54/Rpn10 ubiquitin receptor subunit of the 26S proteasome, which fulfills all the characteristics of a protein stabilization motif (STABILON).

Re-analysis of the Hungarian amyotrophic lateral sclerosis population and evaluation of novel ALS genetic risk variants.

Amyotrophic lateral sclerosis (ALS) is a presently incurable neurodegenerative disease. Some genes have a causal relationship to ALS, others act as susceptibility and/or risk factors. We aimed to elucidate the role of 14 ALS-related genes in the Hungarian ALS population of 183 patients.

Usp14 is required for spermatogenesis and ubiquitin stress responses in .

Deubiquitylating (DUB) enzymes free covalently linked ubiquitin moieties from ubiquitin-ubiquitin and ubiquitin-protein conjugates, and thereby maintain the equilibrium between free and conjugated ubiquitin moieties and regulate ubiquitin-mediated cellular processes. Here, we performed genetic analyses of mutant phenotypes in and demonstrate that loss of Usp14 function results in male sterility, with defects in spermatid individualization and reduced testicular free monoubiquitin levels. These phenotypes were rescued by germline-specific overexpression of wild-type Usp14.

Developmental and tissue specific changes of ubiquitin forms in Drosophila melanogaster.

In most Eukaryotes, ubiquitin either exists as free monoubiquitin or as a molecule that is covalently linked to other proteins. These two forms cycle between each other and due to the concerted antagonistic activity of ubiquitylating and deubiquitylating enzymes, an intracellular ubiquitin equilibrium is maintained that is essential for normal biological function. However, measuring the level and ratio of these forms of ubiquitin has been difficult and time consuming.

The Expression of Checkpoint and DNA Repair Genes in Head and Neck Cancer as Possible Predictive Factors.

DNA damage response failure may influence the efficacy of DNA-damaging treatments. We determined the expression of 16 genes involved in distinct DNA damage response pathways, in association with the response to standard therapy. Twenty patients with locoregionally advanced, squamous cell head and neck carcinoma were enrolled.

Role of the deubiquitylating enzyme DmUsp5 in coupling ubiquitin equilibrium to development and apoptosis in Drosophila melanogaster.

Protein ubiquitylation is a dynamic process that affects the function and stability of proteins and controls essential cellular processes ranging from cell proliferation to cell death. This process is regulated through the balanced action of E3 ubiquitin ligases and deubiquitylating enzymes (DUB) which conjugate ubiquitins to, and remove them from target proteins, respectively. Our genetic analysis has revealed that the deubiquitylating enzyme DmUsp5 is required for maintenance of the ubiquitin equilibrium, cell survival and normal development in Drosophila.

A novel interplay between the ubiquitin–proteasome system and serine proteases during Drosophila development.

The concentrations of the Drosophila proteasomal and extraproteasomal polyubiquitin receptors fluctuate in a developmentally regulated fashion. This fluctuation is generated by a previously unidentified proteolytic activity. In the present paper, we describe the purification, identification and characterization of this protease (endoproteinase I).

CalpB modulates border cell migration in Drosophila egg chambers.

Background: Calpains are calcium regulated intracellular cysteine proteases implicated in a variety of physiological functions and pathological conditions. The Drosophila melanogaster genome contains only two genes, CalpA and CalpB coding for canonical, active calpain enzymes. The movement of the border cells in Drosophila egg chambers is a well characterized model of the eukaryotic cell migration.

lemmingA encodes the Apc11 subunit of the APC/C in Drosophila melanogaster that forms a ternary complex with the E2-C type ubiquitin conjugating enzyme, Vihar and Morula/Apc2.

Background: Ubiquitin-dependent protein degradation is a critical step in key cell cycle events, such as metaphase-anaphase transition and mitotic exit. The anaphase promoting complex/cyclosome (APC/C) plays a pivotal role in these transitions by recognizing and marking regulatory proteins for proteasomal degradation. Its overall structure and function has been elucidated mostly in yeasts and mammalian cell lines.

Overexpression of Dsk2/dUbqln results in severe developmental defects and lethality in Drosophila melanogaster that can be rescued by overexpression of the p54/Rpn10/S5a proteasomal subunit.

Polyubiquitin receptors execute the targeting of polyubiquitylated proteins to the 26S proteasome. In vitro studies indicate that disturbance of the physiological balance among different receptor proteins impairs the proteasomal degradation of polyubiquitylated proteins. To study the physiological consequences of shifting the in vivo equilibrium between the p54/Rpn10 proteasomal and the Dsk2/dUbqln extraproteasomal polyubiquitin receptors, transgenic Drosophila lines were constructed in which the overexpression or RNA interference-mediated silencing of these receptors can be induced.

Developmental-stage-specific regulation of the polyubiquitin receptors in Drosophila melanogaster.

Recognition of polyubiquitylated substrates by the proteasome is a highly regulated process that requires polyubiquitin receptors. We show here that the concentrations of the proteasomal and extraproteasomal polyubiquitin receptors change in a developmentally regulated fashion. The stoichiometry of the proteasomal p54/Rpn10 polyubiquitin receptor subunit, relative to that of other regulatory particle (RP) subunits falls suddenly at the end of embryogenesis, remains low throughout the larval stages, starts to increase again in the late third instar larvae and remains high in the pupae, adults and embryos.

APC/CFzr/Cdh1 promotes cell cycle progression during the Drosophila endocycle.

The endocycle is a commonly observed variant cell cycle in which cells undergo repeated rounds of DNA replication with no intervening mitosis. How the cell cycle machinery is modified to transform a mitotic cycle into endocycle has long been a matter of interest. In both plants and animals, the transition from the mitotic cycle to the endocycle requires Fzr/Cdh1, a positive regulator of the Anaphase-Promoting Complex/Cyclosome (APC/C).

Characterization of the Apc10/Doc1 subunit of the anaphase promoting complex in Drosophila melanogaster.

The anaphase promoting complex or cyclosome (APC/C) is a large protein complex with an ubiquitin ligase activity which specifically targets mitotic regulatory proteins for proteasomal degradation. The APC/C contains at least 11 subunits, most of which are evolutionarily conserved from yeasts to humans. We have isolated and characterized mutant alleles of the gene that codes for the APC10/Doc1 subunit of the Drosophila APC/C.