The enigma of ultraviolet radiation stress granules: Research challenges and new perspectives.

Stress granules (SGs) are non-membrane bound cytoplasmic condensates that form in response to a variety of different stressors. Canonical SGs are thought to have a cytoprotective role, reallocating cellular resources during stress by activation of the integrated stress response (ISR) to inhibit translation and avoid apoptosis. However, different stresses result in compositionally distinct, non-canonical SG formation that is likely pro-apoptotic, though the exact function(s) of both SGs subtypes remain unclear. A unique non-canonical SG subtype is triggered upon exposure to ultraviolet (UV) radiation. While it is generally agreed that UV SGs are bona fide SGs due to their dependence upon the core SG nucleating protein Ras GTPase-activating protein-binding protein 1 (G3BP1), the localization of other key components of UV SGs are unknown or under debate. Further, the dynamics of UV SGs are not known, though unique properties such as cell cycle dependence have been observed. This Perspective compiles the available information on SG subtypes and on UV SGs in particular in an attempt to understand the formation, dynamics, and function of these mysterious stress-specific complexes. We identify key gaps in knowledge related to UV SGs, and examine the unique aspects of their formation. We propose that more thorough knowledge of the distinct properties of UV SGs will lead to new avenues of understanding of the function of SGs, as well as their roles in disease.

Rett syndrome with and without detected MECP2 mutations: an attempt to redefine phenotypes.

BACKGROUND: The diagnosis of Rett syndrome (RTT) is based on a set of clinical criteria, irrespective of mutation status. The aims of this study were (1) to define the clinical differences existing between patients with Rett syndrome with (Group I) and without a MECP2 mutation (Group II), and (2) to characterize the phenotypes associated with the more common MECP2 mutations. PATIENTS AND METHODS: We analyzed 87 patients fulfilling the clinical criteria for RTT. All were observed and videotaped by the same paediatric neurologist. Seven common mutations were considered separately, and associated clinical features analysed. RESULTS: Comparing Group I and II, we found differences concerning psychomotor development prior to onset, acquisition of propositive manipulation and language, and evolving autistic traits. Based on age at observation, we found differences in eye pointing, microcephaly, growth, number of stereotypies, rigidity, ataxia and ataxic-rigid gait, and severity score. Patients with truncating differed from those with missense mutations regarding acquisition of propositive words and independent gait, before the beginning of the disease, and microcephaly, growth, foot length, dystonia, rigidity and severity score, at the time of observation. Patients with the R168X mutation had a more severe phenotype, whereas those with R133C showed a less severe one. Patients with R294X had a hyperactive behaviour, and those with T158M seemed to be particularly ataxic and rigid. CONCLUSION: A clear regressive period (with loss of prehension and language, deceleration of growth) and the presence of more than three different stereotypies, rigidity and ataxic-rigid gait seemed to be very helpful in differentiating Group I from Group II.

Movement disorders in Rett syndrome: an analysis of 60 patients with detected MECP2 mutation and correlation with mutation type.

Rett syndrome (RS) is one of the best human models to study movement disorders. Patients evolve from a hyperkinetic to a hypokinetic state, and a large series of abnormal movements may be observed along their lives such as stereotypies, tremor, chorea, myoclonus, ataxia, dystonia, and rigidity. The aim of this work was to analyze movement disorders in RS patients with a detected MECP2 mutation, as well as their correlation with genotype, in a clinically and genetically well-characterized sample of patients, and thus contribute to redefine the clinical profile of this disease. In this study, we included 60 patients with detected MECP2 mutations. These were categorized and grouped for analysis, according to (1) type of change (missense or truncating, including nonsense and frameshift but also large deletions) and (2) location of the mutation. Differences were found concerning the frequency of independent gait, dystonia, type of tremor, and global score severity when comparing the group of patients with missense and truncating mutations. We also found differences in the presence, distribution, severity, or type of movement disorders in the two groups of patients according to the median duration of the disease (less than 60 months; 60 months or more). We conclude that movement disorders seem to reflect the severity and rate of progression of Rett disorder, patients with truncating mutations presenting a higher rate and more severe dystonia and rigid-akinetic syndrome, when comparing groups with similar time of disease evolution.

Novel synonymous substitution in POMGNT1 promotes exon skipping in a patient with congenital muscular dystrophy.

Walker-Warburg syndrome, muscle-eye-brain disease, Fukuyama congenital muscular dystrophy, congenital muscular dystrophy type 1C, and congenital muscular dystrophy type 1D are overlapping clinical entities belonging to a subgroup of the congenital muscular dystrophies (CMD), collectively designated dystroglycanopathies, in which the common underlying defect is hypoglycosylation of alfa-dystroglycan. Currently, six different genes are known to be implicated in these diseases: POMT1, POMT2, POMGNT1, FCMD, FKRP, and LARGE. We report the molecular characterization of a patient presenting clinical features of CMD and reduced immunostaining for alfa-dystroglycan in muscle. Three candidate genes (FCMD, POMT1 and POMGNT1) were analyzed, and a total of 18 sequence variants were detected: 15 polymorphisms in POMT1 [including three unreported single nucleotide polymorphisms (SNPs)], two polymorphisms in FCMD, and the exonic silent mutation c.636C > T in POMGNT1. Expression analysis revealed that this apparently silent mutation compromises correct premessenger RNA (mRNA) splicing, promoting skipping of the entire exon 7, with a consequent frameshift. In silico analysis of this mutation did not predict alterations in the canonical splice sequences, but rather the creation of a new exonic splice silencer. The recognition of such disease-causing elements may contribute to the further understanding of RNA processing and assist mutation screening in routine diagnosis, where such changes may be underestimated. To aid clinical diagnosis, we generated publicly available LOVD-powered Locus Specific Databases for these three genes and recorded all known sequence variants ( http://www.dmd.nl ).

Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).

Pitt-Hopkins syndrome is a rarely reported syndrome of so-far-unknown etiology characterized by mental retardation, wide mouth, and intermittent hyperventilation. By molecular karyotyping with GeneChip Human Mapping 100K SNP arrays, we detected a 1.2-Mb deletion on 18q21.2 in one patient. Sequencing of the TCF4 transcription factor gene, which is contained in the deletion region, in 30 patients with significant phenotypic overlap revealed heterozygous stop, splice, and missense mutations in five further patients with severe mental retardation and remarkable facial resemblance. Thus, we establish the Pitt-Hopkins syndrome as a distinct but probably heterogeneous entity caused by autosomal dominant de novo mutations in TCF4. Because of its phenotypic overlap, Pitt-Hopkins syndrome evolves as an important differential diagnosis to Angelman and Rett syndromes. Both null and missense mutations impaired the interaction of TCF4 with ASCL1 from the PHOX-RET pathway in transactivating an E box-containing reporter construct; therefore, hyperventilation and Hirschsprung disease in patients with Pitt-Hopkins syndrome might be explained by altered development of noradrenergic derivatives.