@article {958, title = {Autosomal recessive variants in alter the γ-tubulin ring complex leading to neurodevelopmental disease.}, journal = {iScience}, volume = {24}, year = {2021}, month = {2021 Jan 22}, pages = {101948}, abstract = {

Microtubules help building the cytoskeleton of neurons and other cells. Several components of the gamma-tubulin (γ-tubulin) complex have been previously reported in human neurodevelopmental diseases. We describe two siblings from a consanguineous Turkish family with dysmorphic features, developmental delay, brain malformation, and epilepsy carrying a homozygous mutation (p.Glu311Lys) in encoding the γ-tubulin complex 2 (GCP2) protein. This variant is predicted to disrupt the electrostatic interaction of GCP2 with GCP3. In primary fibroblasts carrying the variant, we observed a faint delocalization of γ-tubulin during the cell cycle but normal GCP2 protein levels. Through mass spectrometry, we observed dysregulation of multiple proteins involved in the assembly and organization of the cytoskeleton and the extracellular matrix, controlling cellular adhesion and of proteins crucial for neuronal homeostasis including axon guidance. In summary, our functional and proteomic studies link TUBGCP2 and the γ-tubulin complex to the development of the central nervous system in humans.

}, issn = {2589-0042}, doi = {10.1016/j.isci.2020.101948}, author = {G{\"u}ng{\"o}r, Serdal and Oktay, Yavuz and Hiz, Semra and Aranguren-Ib{\'a}{\~n}ez, {\'A}lvaro and Kalafatcilar, Ipek and Yaramis, Ahmet and Karaca, Ezgi and Yis, Uluc and Sonmezler, Ece and Ekinci, Burcu and Aslan, Mahmut and Yilmaz, Elmasnur and {\"O}zg{\"o}r, Bilge and Balaraju, Sunitha and Szabo, Nora and Laurie, Steven and Beltran, Sergi and MacArthur, Daniel G and Hathazi, Denisa and Topf, Ana and Roos, Andreas and Lochm{\"u}ller, Hanns and Vernos, Isabelle and Horvath, Rita} } @article {960, title = {Expanding the clinical and molecular spectrum of ATP6V1A related metabolic cutis laxa.}, journal = {J Inherit Metab Dis}, year = {2020}, month = {2020 Dec 15}, abstract = {

Several inborn errors of metabolism show cutis laxa as a highly recognizable feature. One group of these metabolic cutis laxa conditions is autosomal recessive cutis laxa type 2 caused by defects in v-ATPase components or the mitochondrial proline cycle. Besides cutis laxa, muscular hypotonia and cardiac abnormalities are hallmarks of autosomal recessive cutis laxa type 2D (ARCL2D) due to pathogenic variants in ATP6V1A encoding subunit A of the v-ATPase. Here, we report on three affected individuals from two families with ARCL2D in whom we performed whole exome and Sanger sequencing. We performed functional studies in fibroblasts from one individual, summarized all known probands{\textquoteright} clinical, molecular, and biochemical features and compared them, also to other metabolic forms of cutis laxa. We identified novel missense and the first nonsense variant strongly affecting ATP6V1A expression. All six ARCL2D affected individuals show equally severe cutis laxa and dysmorphism at birth. While for one no information was available, two died in infancy and three are now adolescents with mild or absent intellectual disability. Muscular weakness, ptosis, contractures, and elevated muscle enzymes indicated a persistent myopathy. In cellular studies, a fragmented Golgi compartment, a delayed Brefeldin A-induced retrograde transport and glycosylation abnormalities were present in fibroblasts from two individuals. This is the second and confirmatory report on pathogenic variants in ATP6V1A as the cause of this extremely rare condition and the first to describe a nonsense allele. Our data highlight the tremendous clinical variability of ATP6V1A related phenotypes even within the same family.

}, issn = {1573-2665}, doi = {10.1002/jimd.12341}, author = {Vogt, Guido and El Choubassi, Naji and Herczegfalvi, {\'A}gnes and K{\"o}lbel, Heike and Lekaj, Anja and Schara, Ulrike and Holtgrewe, Manuel and Krause, Sabine and Horvath, Rita and Schuelke, Markus and H{\"u}bner, Christoph and Mundlos, Stefan and Roos, Andreas and Lochm{\"u}ller, Hanns and Karcagi, Veronika and Kornak, Uwe and Fischer-Zirnsak, Bj{\"o}rn} } @article {755, title = {Severe neurodevelopmental disease caused by a homozygous TLK2 variant.}, journal = {Eur J Hum Genet}, volume = {28}, year = {2020}, month = {2020 03}, pages = {383-387}, abstract = {

A distinct neurodevelopmental phenotype characterised mainly by mild motor and language delay and facial dysmorphism, caused by heterozygous de novo or dominant variants in the TLK2 gene has recently been described. All cases reported carried either truncating variants located throughout the gene, or missense changes principally located at the C-terminal end of the protein mostly resulting in haploinsufficiency of TLK2. Through whole exome sequencing, we identified a homozygous missense variant in TLK2 in a patient showing more severe symptoms than those previously described, including cerebellar vermis hypoplasia and West syndrome. Both parents are heterozygous for the variant and clinically unaffected highlighting that recessive variants in TLK2 can also be disease causing and may act through a different pathomechanism.

}, keywords = {Adult, Cerebellum, Child, Developmental Disabilities, Female, Heterozygote, Homozygote, Humans, Infant, Male, Mutation, Missense, Nervous System Malformations, Pedigree, Protein Kinases, Spasms, Infantile}, issn = {1476-5438}, doi = {10.1038/s41431-019-0519-x}, author = {Topf, Ana and Oktay, Yavuz and Balaraju, Sunitha and Yilmaz, Elmasnur and Sonmezler, Ece and Yis, Uluc and Laurie, Steven and Thompson, Rachel and Roos, Andreas and MacArthur, Daniel G and Yaramis, Ahmet and G{\"u}ng{\"o}r, Serdal and Lochm{\"u}ller, Hanns and Hiz, Semra and Horvath, Rita} }