Mutations in the WWOX gene cause a broad range of ultra-rare neurodevelopmental and brain degenerative disorders, associated with a high likelihood of premature death in animal models as well as in ...humans. The encoded Wwox protein is a WW domain-containing oxidoreductase that participates in crucial biological processes including tumour suppression, cell growth/differentiation and regulation of steroid metabolism, while its role in neural development is less understood. We analyzed the exomes of a family affected with multiple pre- and postnatal anomalies, including cerebellar vermis hypoplasia, severe neurodevelopmental impairment and refractory epilepsy, and identified a segregating homozygous WWOX mutation leading to a premature stop codon. Abnormal cerebral cortex development due to a defective architecture of granular and molecular cell layers was found in the developing brain of a WWOX-deficient human foetus from this family. A similar disorganization of cortical layers was identified in lde/lde rats (carrying a homozygous truncating mutation which disrupts the active C-terminal domain) investigated at perinatal stages. Transcriptomic analyses of Wwox-depleted human neural progenitor cells showed an impaired expression of a number of neuronal migration-related genes encoding for tubulins, kinesins and associated proteins. These findings indicate that loss of Wwox may affect different cytoskeleton components and alter prenatal cortical development, highlighting a regulatory role of the WWOX gene in neural progenitor cells and migrating neurons across different species.
Collagen VI is a heterotrimeric protein expressed in several tissues and involved in the maintenance of cell integrity. It localizes at the cell surface, creating a microfilamentous network that ...links the cytoskeleton to the extracellular matrix. The heterotrimer consists of three chains encoded by
,
and
genes. Recessive and dominant molecular defects cause two main disorders, the severe Ullrich congenital muscular dystrophy and the relatively mild and slowly progressive Bethlem myopathy. We analyzed the clinical aspects, pathological features and mutational spectrum of 15 COL6-mutated patients belonging to our cohort of muscular dystrophy probands. Patients presented a heterogeneous phenotype ranging from severe forms to mild adult-onset presentations. Molecular analysis by NGS detected 14 different pathogenic variants, three of them so far unreported. Two changes, localized in the triple-helical domain of COL6A1, were associated with a more severe phenotype. Histological, immunological and ultrastructural techniques were employed for the validation of the genetic variants; they documented the high variability in COL6 distribution and the extracellular matrix disorganization, highlighting the clinical heterogeneity of our cohort. The combined use of these different technologies is pivotal in the diagnosis of COL6 patients.
The human microbiota is an integral component in the maintenance of health and of the immune system. Microbiome-wide association studies have found numerous diseases associated to dysbiosis. Studies ...are needed to move beyond correlations and begin to address causation. Autoimmune thyroid diseases (ATD) are one of the most common organ-specific autoimmune disorders with an increasing prevalence, higher than 5% worldwide. Most frequent manifestations of ATD are Hashimoto's thyroiditis and Graves' disease. The exact etiology of ATD remains unknown. Until now it is not clear whether bacterial infections can trigger ATD or modulate the efficacy of treatment and prognosis. The aim of our review is to characterize the microbiota and in ATD and to evaluate the impact of dysbiosis on treatment and prognosis. Moreover, variation of gut microbiome has been associated with thyroid cancer and benign nodules. Here we will characterize the microbioma in benign thyroid nodules, and papillary thyroid cancer to evaluate their implications in the pathophysiology and progression.
Noonan syndrome is an autosomal dominant developmental disorder characterized by peculiar facial dysmorphisms, short stature, congenital heart defects, and hypertrophic cardiomyopathy. In 2001,
was ...identified as the first Noonan syndrome gene and is responsible for the majority of Noonan syndrome cases. Over the years, several other genes involved in Noonan syndrome (
,
,
,
,
,
,
, and
) have been identified, acting at different levels of the RAS-mitogen-activated protein kinase pathway. Recently,
was recognized as a novel Noonan syndrome gene with autosomal recessive inheritance, and only four families have been described to date. Here, we report the first Italian case, a one-year-old child with left ventricular hypertrophy, moderate pulmonary valve stenosis, and atrial septal defect, with a clinical suspicion of RASopathy supported by the presence of typical Noonan-like facial features and short stature. Exome sequencing identified a novel homozygous loss-of-function variant in the exon 3 of
(NM_181784.3:c.325del; p.Arg109Glufs*7), likely causing nonsense-mediated decay. Our results and the presented clinical data may help us to further understand and dissect the genetic heterogeneity of Noonan syndrome.
Using deep phenotyping and high-throughput sequencing, we have identified a novel type of distal myopathy caused by mutations in the Small muscle protein X-linked (
SMPX
) gene. Four different ...missense mutations were identified in ten patients from nine families in five different countries, suggesting that this disease could be prevalent in other populations as well. Haplotype analysis of patients with similar ancestry revealed two different founder mutations in Southern Europe and France, indicating that the prevalence in these populations may be higher. In our study all patients presented with highly similar clinical features: adult-onset, usually distal more than proximal limb muscle weakness, slowly progressing over decades with preserved walking. Lower limb muscle imaging showed a characteristic pattern of muscle involvement and fatty degeneration. Histopathological and electron microscopic analysis of patient muscle biopsies revealed myopathic findings with rimmed vacuoles and the presence of sarcoplasmic inclusions, some with amyloid-like characteristics. In silico predictions and subsequent cell culture studies showed that the missense mutations increase aggregation propensity of the SMPX protein. In cell culture studies, overexpressed SMPX localized to stress granules and slowed down their clearance.
Limb-girdle muscular dystrophies (LGMD) are genetically and clinically heterogeneous conditions. We investigated a large family with autosomal dominant transmission pattern, previously classified as ...LGMD1F and mapped to chromosome 7q32. Affected members are characterized by muscle weakness affecting earlier the pelvic girdle and the ileopsoas muscles. We sequenced the whole exome of four family members and identified a shared heterozygous frame-shift variant in the Transportin 3 (TNPO3) gene, encoding a member of the importin-β super-family. The TNPO3 gene is mapped within the LGMD1F critical interval and its 923-amino acid human gene product is also expressed in skeletal muscle. In addition, we identified an isolated case of LGMD with a new missense mutation in the same gene. We localized the mutant TNPO3 around the nucleus, but not inside. The involvement of gene related to the nuclear transport suggests a novel disease mechanism leading to muscular dystrophy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Defects in the motor domain of kinesin family member 1A (KIF1A), a neuron‐specific ATP‐dependent anterograde axonal transporter of synaptic cargo, are well‐recognized to cause a spectrum of ...neurological conditions, commonly known as KIF1A‐associated neurological disorders (KAND). Here, we report one mutation‐negative female with classic Rett syndrome (RTT) harboring a de novo heterozygous novel variant NP_001230937.1:p.(Asp248Glu) in the highly conserved motor domain of KIF1A. In addition, three individuals with severe neurodevelopmental disorder along with clinical features overlapping with KAND are also reported carrying de novo heterozygous novel NP_001230937.1:p.(Cys92Arg) and p.(Pro305Leu) or previously reported NP_001230937.1:p.(Thr99Met) variants in KIF1A. In silico tools predicted these variants to be likely pathogenic, and 3D molecular modeling predicted defective ATP hydrolysis and/or microtubule binding. Using the neurite tip accumulation assay, we demonstrated that all novel KIF1A variants significantly reduced the ability of the motor domain of KIF1A to accumulate along the neurite lengths of differentiated SH‐SY5Y cells. In vitro microtubule gliding assays showed significantly reduced velocities for the variant p.(Asp248Glu) and reduced microtubule binding for the p.(Cys92Arg) and p.(Pro305Leu) variants, suggesting a decreased ability of KIF1A to move along microtubules. Thus, this study further expanded the phenotypic characteristics of KAND individuals with pathogenic variants in the KIF1A motor domain to include clinical features commonly seen in RTT individuals.
KIF1A‐associated Neurological Disorders (KANDs): functional validation of identified variants.
The gene DST encodes for the large protein BPAG1 involved in hemidesmosomes. Its alternative splicing gives rise to tissue‐enriched isoforms in brain, muscle, and skin. The few patients described so ...far with bi‐allelic mutations in the DST gene have either a skin phenotype of epidermolysis bullosa simplex or a neurological phenotype. Here, we report a 17‐year‐old female individual presenting with a more complex phenotype consisting of both skin and neuronal involvement, in addition to several previously unreported findings, such as iris heterochromia, cataract, hearing impairment, syringomyelia, behavioral, and gastrointestinal issues, osteoporosis, and growth hormone deficiency. Family‐trio whole exome sequencing revealed that she was a compound heterozygous for two variants in the DST gene with highly‐predicted functional impact, c.3886A>G (p.R1296X) in exon 29 and c.806C>T (p.H269R) in exon 7. Interestingly, exon 7 is included in the neuronal isoform whereas exon 29 is expressed in both skin and neuronal isoforms. The patient we described is the first case with a mutation affecting an exon expressed in both the neuronal and skin isoforms that can explain the more complex phenotype compared to previously reported cases.
Progressive cardiac conduction disease (PCCD) is a relatively common condition in young and elderly populations, related to rare mutations in several genes, including
and
Familial cases have also ...been reported. We describe a family with a large number of individuals necessitating pacemaker implantation, likely due to varying degrees of PCCD. The proband is a 47-year-old-patient, whose younger brother died at 25 years of unexplained sudden cardiac death. Three paternal uncles needed a pacemaker (PM) implantation between 40 and 65 years for unspecified causes. At the age of 42, he was implanted with a PM for two episodes of syncope and the presence of complete atrioventricular block (AVB). NGS analysis revealed the missense variation c. 2351G>A, p.Gly844Asp in the exon 17 of the TRPM4 gene. This gene encodes the TRPM4 channel, a calcium-activated nonselective cation channel of the transient receptor potential melastatin (TRPM) ion channel family. Variations in
have been shown to cause an increase in cell surface current density, which results in a gain of gene function. Our report broadens and supports the causative role of
gene mutations in PCCD. Genetic screening and identification of the causal mutation are critical for risk stratification and family counselling.
We describe a family with a novel TNPO3 mutation of limb–girdle muscular dystrophy D2 (or LGMD 1F), a rare muscle disorder with autosomal dominant inheritance, first identified in an Italo-Spanish ...family where the causative defect has been found to be due to TNPO3 gene mutation, encoding transportin-3 protein (TNPO3). We present the clinical, histopathological and muscle magnetic resonance imaging (MRI) features in two patients, mother and son Hungarian origin, affected by LGMD D2 and correlate their clinical, MRI and histopathological data found in this condition. The affected son presented early pelvic girdle muscle weakness and thin muscles similar to a congenital myopathy; the mother was less compromised and had an LGMD phenotype. Muscle MRI showed a very pronounced lower limb muscle atrophy in both patients. The most relevant change obtained in the child muscle biopsy was a generalized type 1 fibre atrophy. The two patients presented the same mutation, but a different phenotype has been observed in mother and son.
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