CLP1 Founder Mutation Links tRNA Splicing and Maturation to Cerebellar Development and Neurodegeneration

SummaryNeurodegenerative 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

Newly Described Clinical Features in Two Siblings With MACS Syndrome and a Novel Mutation in RIN2

The disorder comprising Macrocephaly, Alopecia, Cutis laxa, and Scoliosis has been designated MACS syndrome. It is a rare condition, inherited in an autosomal recessive pattern. Three families from different ethnic origins have so far been reported and were all linked to homozygous mutations in RIN2, a gene encoding the Ras and Rab interactor 2 protein involved in cell trafficking. We describe herein the fourth family with MACS syndrome in two siblings carrying a novel homozygous mutation, c.1878_1879insC in exon 8 of the RIN2 gene, which predicts p.Ile627Hisfs*7. We also report on additional findings not previously described in MACS syndrome, including bronchiectasis and hypergonadotropic hypogonadism. Finally, our overall data support the argument that RIN2 syndrome is a more appropriate name for the disorder. (c) 2013 Wiley Periodicals, Inc

Homozygous shox gene deletion detected by array CGH in a girl with langer mesomelic dysplasia

Langer mesomelic dysplasia (LMD) is characterized by hypomelia with severehypoplasia of ulnae and ibulae, and bowed, thickened radii and tibiae,causing deformities of the hands and feet. LMD is caused by homozygousmutations in the SHOX/SHOXY (short stature homoebox) gene, of whichheterozygous mutations or deletions cause Leri-Weil Dysplasia (LWD).Phenotype of LWD can be incomplete between and within families. We presenta 13 year old female with LMD, the second child of healthy irst cousinparents. She had micrognathia, disproportionate short stature with variousmusculoskeletal indings (absence of the distal lexion creases of the 3rd,4th, 5th ingers on the right, camptodactyly of the 3rd, 4th, 5th ingers onthe left, tibial bowing). X-rays revealed hypoplasia of ulnae, ibulae and themandible. Chromosome analysis and FISH investigation by using SHOX geneprobe revealed normal results. Sequence analysis failed due to unsuccessfulPCR ampliications. Array comparative genomic hybridization (a-CGH) studyshowed a 174 kb homozygous deletion, encompassing the SHOX gene.Proband‘s parents were heterozygous for the same deletion by a-CGH. FISHwas uninformative, because there was no difference between the intensityof the signals on both chromosomes. Since the primers used were locatedwithin the deleted region, molecular studies could not be performed. A-CGHproved to be the most powerful diagnostic tool in this case