@article {140, title = {Phenotypic Expansion of Congenital Disorder of Glycosylation Due to SRD5A3 Null Mutation.}, journal = {JIMD Rep}, volume = {26}, year = {2016}, month = {2016}, pages = {7-12}, abstract = {

We present a boy, admitted at 4 months, with facial dysmorphism, hypertrichosis, loose skin, bilateral inguinal hernia, severe hypotonia, psychomotor disability, seizures with hypsarrhythmia (West syndrome), hepatosplenomegaly, increased serum transaminases, iris coloboma, glaucoma, corneal clouding and bilateral dilated lateral ventricles, and extra-axial post-cerebellar space. Serum transferrin isoelectrofocusing (IEF) showed a type 1 pattern. Whole-exome genotyping showed a previously reported homozygous nonsense mutation c.320G>A; p.Trp107X in SRD5A3. Epilepsy and glaucoma have been reported only once in the 19 described SRD5A3-congenital glycosylation defect patients, and corneal clouding not at all.

}, issn = {2192-8304}, doi = {10.1007/8904_2015_478}, author = {Tuysuz, Beyhan and Pehlivan, Davut and {\"O}zk{\"o}k, Ahmet and Jhangiani, Shalini and Yalcinkaya, Cengiz and Zeybek, {\c C}i{\u g}dem Aktu{\u g}lu and Muzny, Donna Marie and Lupski, James R and Gibbs, Richard and Jaeken, Jaak} } @article {252, title = {CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration.}, journal = {Cell}, volume = {157}, year = {2014}, month = {2014 Apr 24}, pages = {651-63}, abstract = {

Neurodegenerative diseases can occur so early as to affect neurodevelopment. From a cohort of more than 2,000 consanguineous families with childhood neurological disease, we identified a founder mutation in four independent pedigrees in cleavage and polyadenylation factor I subunit 1 (CLP1). CLP1 is a multifunctional kinase implicated in tRNA, mRNA, and siRNA maturation. Kinase activity of the CLP1 mutant protein was defective, and the tRNA endonuclease complex (TSEN) was destabilized, resulting in impaired pre-tRNA cleavage. Germline clp1 null zebrafish showed cerebellar neurodegeneration that was rescued by wild-type, but not mutant, human CLP1 expression. Patient-derived induced neurons displayed both depletion of mature tRNAs and accumulation of unspliced pre-tRNAs. Transfection of partially processed tRNA fragments into patient cells exacerbated an oxidative stress-induced reduction in cell survival. Our data link tRNA maturation to neuronal development and neurodegeneration through defective CLP1 function in humans.

}, keywords = {Animals, Brain, Cerebellum, Cleavage And Polyadenylation Specificity Factor, Female, Humans, Male, Mice, Models, Molecular, Neurodegenerative Diseases, Nuclear Proteins, Pedigree, Phosphotransferases, RNA Splicing, RNA, Transfer, Saccharomyces cerevisiae, Transcription Factors, Zebrafish, Zebrafish Proteins}, issn = {1097-4172}, doi = {10.1016/j.cell.2014.03.049}, author = {Schaffer, Ashleigh E and Eggens, Veerle R C and {\c C}a{\u g}layan, Ahmet Okay and Reuter, Miriam S and Scott, Eric and Coufal, Nicole G and Silhavy, Jennifer L and Xue, Yuanchao and Kayserili, H{\"u}lya and Yasuno, Katsuhito and Rosti, Rasim Ozgur and Abdellateef, Mostafa and Caglar, Caner and Kasher, Paul R and Cazemier, J Leonie and Weterman, Marian A and Cantagrel, Vincent and Cai, Na and Zweier, Christiane and Altunoglu, Umut and Satkin, N Bilge and Aktar, Fesih and Tuysuz, Beyhan and Yalcinkaya, Cengiz and Caksen, Huseyin and Bilguvar, Kaya and Fu, Xiang-Dong and Trotta, Christopher R and Gabriel, Stacey and Reis, Andr{\'e} and G{\"u}nel, Murat and Baas, Frank and Gleeson, Joseph G} } @article {311, title = {Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration.}, journal = {Proc Natl Acad Sci U S A}, volume = {110}, year = {2013}, month = {2013 Feb 26}, pages = {3489-94}, abstract = {

Ubiquitin C-terminal hydrolase-L1 (UCHL1), a neuron-specific de-ubiquitinating enzyme, is one of the most abundant proteins in the brain. We describe three siblings from a consanguineous union with a previously unreported early-onset progressive neurodegenerative syndrome featuring childhood onset blindness, cerebellar ataxia, nystagmus, dorsal column dysfuction, and spasticity with upper motor neuron dysfunction. Through homozygosity mapping of the affected individuals followed by whole-exome sequencing of the index case, we identified a previously undescribed homozygous missense mutation within the ubiquitin binding domain of UCHL1 (UCHL1(GLU7ALA)), shared by all affected subjects. As demonstrated by isothermal titration calorimetry, purified UCHL1(GLU7ALA), compared with WT, exhibited at least sevenfold reduced affinity for ubiquitin. In vitro, the mutation led to a near complete loss of UCHL1 hydrolase activity. The GLU7ALA variant is predicted to interfere with the substrate binding by restricting the proper positioning of the substrate for tunneling underneath the cross-over loop spanning the catalytic cleft of UCHL1. This interference with substrate binding, combined with near complete loss of hydrolase activity, resulted in a >100-fold reduction in the efficiency of UCHL1(GLU7ALA) relative to WT. These findings demonstrate a broad requirement of UCHL1 in the maintenance of the nervous system.

}, keywords = {Adult, Age of Onset, Amino Acid Sequence, Base Sequence, Child, Preschool, Exome, Female, Genes, Recessive, Homozygote, Humans, Hydrolysis, Male, Models, Molecular, Molecular Sequence Data, Mutation, Missense, Nerve Degeneration, Neurons, Pedigree, Protein Binding, Sequence Analysis, DNA, Substrate Specificity, Syndrome, Thermodynamics, Ubiquitin, Ubiquitin Thiolesterase}, issn = {1091-6490}, doi = {10.1073/pnas.1222732110}, author = {Bilguvar, Kaya and Tyagi, Navneet K and Ozkara, Cigdem and Tuysuz, Beyhan and Bakircioglu, Mehmet and Choi, Murim and Delil, Sakir and {\c C}a{\u g}layan, Ahmet O and Baranoski, Jacob F and Erturk, Ozdem and Yalcinkaya, Cengiz and Karacorlu, Murat and Dincer, Alp and Johnson, Michele H and Mane, Shrikant and Chandra, Sreeganga S and Louvi, Angeliki and Boggon, Titus J and Lifton, Richard P and Horwich, Arthur L and G{\"u}nel, Murat} }