@article {749, title = {A missense mutation in the catalytic domain of O-GlcNAc transferase links perturbations in protein O-GlcNAcylation to X-linked intellectual disability.}, journal = {FEBS Lett}, volume = {594}, year = {2020}, month = {2020 02}, pages = {717-727}, abstract = {

X-linked intellectual disabilities (XLID) are common developmental disorders. The enzyme O-GlcNAc transferase encoded by OGT, a recently discovered XLID gene, attaches O-GlcNAc to nuclear and cytoplasmic proteins. As few missense mutations have been described, it is unclear what the aetiology of the patient phenotypes is. Here, we report the discovery of a missense mutation in the catalytic domain of OGT in an XLID patient. X-ray crystallography reveals that this variant leads to structural rearrangements in the catalytic domain. The mutation reduces in~vitro OGT activity on substrate peptides/protein. Mouse embryonic stem cells carrying the mutation reveal reduced O-GlcNAcase (OGA) and global O-GlcNAc levels. These data suggest a direct link between changes in the O-GlcNAcome and intellectual disability observed in patients carrying OGT mutations.

}, keywords = {Animals, Catalytic Domain, Cell Line, Glycosylation, Humans, Intellectual Disability, Mice, Models, Molecular, Mutation, Missense, N-Acetylglucosaminyltransferases}, issn = {1873-3468}, doi = {10.1002/1873-3468.13640}, author = {Pravata, Veronica M and Gundogdu, Mehmet and Bartual, Sergio G and Ferenbach, Andrew T and Stavridis, Marios and {\~O}unap, Katrin and Pajusalu, Sander and {\v Z}ordania, Riina and Wojcik, Monica H and van Aalten, Daan M F} } @article {726, title = {PEHO syndrome caused by compound heterozygote variants in ZNHIT3 gene.}, journal = {Eur J Med Genet}, volume = {63}, year = {2020}, month = {2020 Feb}, pages = {103660}, abstract = {

PEHO syndrome is characterized by Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy, which was first described in Finnish patients. A homozygous missense substitution p.Ser31Leu in ZNHIT3 was recently identified as the primary cause of PEHO syndrome in Finland. Variants in ZNHIT3 have not been identified in patients with PEHO or PEHO-like syndrome in other populations. It has therefore been suggested that PEHO syndrome caused by ZNHIT3 variants does not occur outside of the Finnish population. We describe the first patient outside Finland who carries compound heterozygous variants in ZNHIT3 gene causing PEHO syndrome. Trio genome sequencing was carried out and the identified variants were confirmed by Sanger sequencing. The patient filled all diagnostic clinical criteria of PEHO syndrome. We identified biallelic missense variants in ZNHIT3 gene: the c.92C > T p.(Ser31Leu) variant (NM_004773.3), which is described previously as causing PEHO syndrome and the second novel variant c.41G > T p.(Cys14Phe). There are only eight heterozygous carriers of c.41G > T variant in the gnomAD database and it is predicted damaging by multiple in silico algorithms. The ZNHIT3-associated PEHO syndrome exists outside of the Finnish population.

}, keywords = {Brain Edema, Databases, Genetic, Edema, Epileptic Syndromes, Female, Finland, Heterozygote, Humans, Infant, Newborn, Mutation, Missense, Neurodegenerative Diseases, Nuclear Proteins, Optic Atrophy, Phenotype, Spasms, Infantile, Transcription Factors, Whole Exome Sequencing, Whole Genome Sequencing}, issn = {1878-0849}, doi = {10.1016/j.ejmg.2019.04.017}, author = {{\~O}unap, Katrin and Muru, Kai and {\~O}iglane-Shlik, Eve and Ilves, Pilvi and Pajusalu, Sander and Kuus, Imbi and Wojcik, Monica H and Reimand, Tiia} } @article {491, title = {Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 05 03}, pages = {744-759}, abstract = {

RORĪ±, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D.~rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in~vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome.

}, keywords = {Adolescent, Adult, Aged, 80 and over, Alleles, Animals, Autistic Disorder, Brain, Cerebellar Ataxia, Child, Child, Preschool, Disease Models, Animal, DNA Copy Number Variations, Female, Genes, Dominant, Genetic Complementation Test, Humans, Intellectual Disability, Larva, Magnetic Resonance Imaging, Male, Middle Aged, Mutation, Missense, Nuclear Receptor Subfamily 1, Group F, Member 1, Purkinje Cells, Syndrome, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.02.021}, author = {Guissart, Claire and Latypova, X{\'e}nia and Rollier, Paul and Khan, Tahir N and Stamberger, Hannah and McWalter, Kirsty and Cho, Megan T and Kjaergaard, Susanne and Weckhuysen, Sarah and Lesca, Gaetan and Besnard, Thomas and {\~O}unap, Katrin and Schema, Lynn and Chiocchetti, Andreas G and McDonald, Marie and de Bellescize, Julitta and Vincent, Marie and Van Esch, Hilde and Sattler, Shannon and Forghani, Irman and Thiffault, Isabelle and Freitag, Christine M and Barbouth, Deborah Sara and Cadieux-Dion, Maxime and Willaert, Rebecca and Guillen Sacoto, Maria J and Safina, Nicole P and Dubourg, Christ{\`e}le and Grote, Lauren and Carr{\'e}, Wilfrid and Saunders, Carol and Pajusalu, Sander and Farrow, Emily and Boland, Anne and Karlowicz, Danielle Hays and Deleuze, Jean-Fran{\c c}ois and Wojcik, Monica H and Pressman, Rena and Isidor, Bertrand and Vogels, Annick and Van Paesschen, Wim and Al-Gazali, Lihadh and Al Shamsi, Aisha Mohamed and Claustres, Mireille and Pujol, Aurora and Sanders, Stephan J and Rivier, Fran{\c c}ois and Leboucq, Nicolas and Cogn{\'e}, Benjamin and Sasorith, Souphatta and Sanlaville, Damien and Retterer, Kyle and Odent, Sylvie and Katsanis, Nicholas and B{\'e}zieau, St{\'e}phane and Koenig, Michel and Davis, Erica E and Pasquier, Laurent and K{\"u}ry, S{\'e}bastien} }