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

Microcephaly, Dysmorphic Features, Corneal Dystrophy, Hairy Nipples, Underdeveloped Labioscrotal Folds, and Small Cerebellum in Four Patients

Pontocerebellar hypoplasia (PCH) can occur as an isolated entity or part of a syndrome. PCH has been reported with facial dysmorphism, ocular anomalies, and genital anomalies, but the co-occurrence of all four has not been previously described. We report on four patients, born to two consanguineous families that are not related to one another, with distinctive facial features (short forehead, laterally extended, medially flared eyebrows), corneal dystrophy, underdevelopment of labioscrotal folds, and nonprogressive PCH. In addition, the patients show hair extruding from the lactiferous ducts, which to our knowledge has not been described before. The parental consanguinity, affected siblings of both genders, and absent manifestations in parents, indicate an autosomal recessive pattern of inheritance as most likely. (C) 2016 Wiley Periodicals, Inc

Türk Noonan Sendromlu Hastalarda Genotip Fenotip İlişkisi

Amaç: Çalışmamız, moleküler düzeyde tanısı kesinleşmiş 15 Noonan sendromu olgusunun klinik ve moleküler bulgularını gözden geçirerek literatür ışığında genotip-fenotip ilişkisini tartışan, Türkiye için ilk ve özgün bir çalışmadır. Gereç ve Yöntemler: İstanbul Üniversitesi İstanbul Tıp Fakültesi Tıbbi Genetik Anabilim Dalına başvurmuş ve Noonan sendromu klinik tanısı almış 35 hasta, Leuven Katolik Üniversitesi İnsan Genetiği Departmanında Noonan sendromuna yol açan dört gendeki -PTPN11, SOS1, KRAS ve RAF1- mutasyonlar açısından analiz edilmiştir. Bulgular: Noonan sendromu klinik tanısı ile değerlendirilen 35 hasta içinden moleküler çalışmalar sonucunda 13'ünde PTPN11 mutasyonu gösterilirken, 1'er hastada KRAS ve RAF1 mutasyonu gösterilmiş ve bu hastaların klinik bulguları değerlendirilmiştir. Tipik yüz görünümü (%87), pektus deformitesi (%67) ve erkeklerde kriptorşidizm (%75) mutasyon-pozitif 15 hastada en sık rastlanan özelliklerdi. Sadece PTPN11 geninde mutasyon taşıyan olguların moleküler ve klinik bulguları genotip-fenotip ilişkisi üzerine yazılmış literatür ışığında tartışıldı. Olgu serimizde PTPN11 geninde en sık gözlenen 923A>G mutasyonuydu, ikinci sırada ise 922A>G mutasyonu gözlendi. 922A>G mutasyonunu taşıyan bireylerin özel eğitime gereksinimlerinin belirgin olmaması ile ilişkili literatür bilgisi, çalışmamız verisi ile de desteklenmektedir. Sonuç: Noonan sendromu hastalarında özellikle hematolojik malignitelere yatkınlık iyi tanımlanmış olmasına rağmen, literatürde sadece 5 olguda sinir sistemi neoplazileri bildirilmiştir. PTPN11 geninde 923A>G mutasyonu saptanan bir olgumuzda sınıf II astrositoma gelişimi, bu yöndeki literatüre olası katkı açısından anlamlıdır

A de novo complex chromosomal rearrangement involving chromosomes 2, 8 and 13 in a dysmorphic case with polysyndactyly

We report herein a case with dysmorphic features, polysyndactyly and psychomotor mental retardation, who had an apparently balanced de novo translocation between chromosomes 8 and 13 as well as a de novo insertion within chromosome 2 itself

Gorlin-chaudhry-moss syndrome revisited: Expanding the phenotype

Gorlin-Chaudhry-Moss syndrome (OMIM 233500) is a rare congenital malformation syndrome with the cardinal manifestations of craniofacial dysostosis, hypertrichosis, underdeveloped genitalia, ocular, and dental anomalies. Since 1960, only six affected individuals have been reported. We report a 4-year and 6-month-old female patient with this phenotype and review the clinical presentation of all patients known so far. Previously unreported malformations of the extremities, larynx, and nose are also described, expanding the phenotype of this rare syndrome. Array-CGH analysis did not show pathological deletions or duplications. (c) 2013 Wiley Periodicals, Inc