The major spliceosome contains five small nuclear RNAs (snRNAs; U1, U2, U4, U5 and U6) essential for splicing. Variants in RNU4-2, encoding U4, cause a neurodevelopmental disorder called ReNU syndrome. We investigated de novo variants in 50 snRNA-encoding genes in a French cohort of 23,649 individuals with rare disorders and gathered additional cases through international collaborations. Altogether, we identified 145 previously unreported probands with (likely) pathogenic variants in RNU4-2 and 21 individuals with de novo and/or recurrent variants in RNU5B-1 and RNU5A-1, encoding U5. Pathogenic variants typically arose de novo on the maternal allele and cluster in regions critical for splicing. RNU4-2 variants mainly localize to two structures, the stem III and T-loop/quasi-pseudoknot, which position the U6 ACAGAGA box for 5′ splice site recognition and associate with different phenotypic severity. RNU4-2 variants result in specific defects in alternative 5′ splice site usage and methylation patterns (episignatures) that correlate with variant location and clinical severity. This study establishes RNU5B-1 as a neurodevelopmental disorder gene, suggests RNU5A-1 as a strong candidate and highlights the role of de novo variants in snRNAs.

Chronic pain is a multidimensional experience that not only includes changes in nociception, but also impairments in emotion and cognitive functions. These last 2 components are not often taken into account in preclinical research. We investigated emotional and cognitive impairments in a model of neuropathic pain in rats induced by chronic constriction injury (CCI) of the sciatic nerve. Nociceptive response, anxiety and depressive-like behaviours as well as cognitive capacities were analysed, and the effect of per os administration of duloxetine and gabapentin was studied. In the electronic von Frey test, CCI rats exhibited mechanical hypersensitivity which can be influenced by duloxetine (3-30 mg/kg) and gabapentin (10-30 mg/kg). Cognitive impairments were found in the social but not in the spatial (Y-maze) recognition memory tests. Duloxetine and gabapentin dose-dependently (3-30 mg/kg) restored social recognition memory impairment. Anxiety-like behaviour was only observed in the open-field test (decrease in the time spent in the inner zone) but not in the elevated plus maze or in the social interactions tests in CCI animals. In this test, impairment in locomotor activity (decrease of the total number of crossing) was also observed. Duloxetine and gabapentin (10mg/kg) were effective to increase the time spent in the inner zone as well as locomotor activity. No difference was observed in depressive-like behaviour (saccharin preference test) between sham-operated and CCI rats. These data suggest that cognitive rather than emotional impairments seem to be present in neuropathic CCI rats and can be reversed by duloxetine and gabapentin.

Genetic diseases have been historically segregated into rare Mendelian disorders and common complex conditions. Large-scale studies using genome sequencing are eroding this distinction and are gradually unmasking the underlying complexity of human traits. Here, we analysed data from the Genomics England 100,000 Genomes Project and from a cohort of 1313 individuals with albinism aiming to gain insights into the genetic architecture of this archetypal rare disorder. We investigated the contribution of protein-coding and regulatory variants both rare and common. We focused on TYR, the gene encoding tyrosinase, and found that a high-frequency promoter variant, TYR c.−301C>T [rs4547091], modulates the penetrance of a prevalent, albinism-associated missense change, TYR c.1205G>A (p.Arg402Gln) [rs1126809]. We also found that homozygosity for a haplotype formed by three common, functionally-relevant variants, TYR c.[−301C;575C>A;1205G>A], is associated with a high probability of receiving an albinism diagnosis (OR>82). This genotype is also associated with reduced visual acuity and with increased central retinal thickness in UK Biobank participants. Finally, we report how the combined analysis of rare and common variants can increase diagnostic yield and can help inform genetic counselling in families with albinism.

Phosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life. Here we used whole exome or genome sequencing to identify 10 unrelated patients harbouring biallelic variants in PI4KA that caused a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients’ fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells. In conclusion, we report a novel severe metabolic disorder caused by PI4KA malfunction, highlighting the importance of phosphoinositide signalling in human brain development and the myelin sheath.