RESUMO
RNA modifications play a fundamental role in cellular function. Pseudouridylation, the most abundant RNA modification, is catalyzed by the H/ACA small ribonucleoprotein (snoRNP) complex that shares four core proteins, dyskerin (DKC1), NOP10, NHP2, and GAR1. Mutations in DKC1, NOP10, or NHP2 cause dyskeratosis congenita (DC), a disorder characterized by telomere attrition. Here, we report a phenotype comprising nephrotic syndrome, cataracts, sensorineural deafness, enterocolitis, and early lethality in two pedigrees: males with DKC1 p.Glu206Lys and two children with homozygous NOP10 p.Thr16Met. Females with heterozygous DKC1 p.Glu206Lys developed cataracts and sensorineural deafness, but nephrotic syndrome in only one case of skewed X-inactivation. We found telomere attrition in both pedigrees, but no mucocutaneous abnormalities suggestive of DC. Both mutations fall at the dyskerin-NOP10 binding interface in a region distinct from those implicated in DC, impair the dyskerin-NOP10 interaction, and disrupt the catalytic pseudouridylation site. Accordingly, we found reduced pseudouridine levels in the ribosomal RNA (rRNA) of the patients. Zebrafish dkc1 mutants recapitulate the human phenotype and show reduced 18S pseudouridylation, ribosomal dysregulation, and a cell-cycle defect in the absence of telomere attrition. We therefore propose that this human disorder is the consequence of defective snoRNP pseudouridylation and ribosomal dysfunction.
Assuntos
Catarata/genética , Proteínas de Ciclo Celular/genética , Enterocolite/genética , Perda Auditiva Neurossensorial/genética , Síndrome Nefrótica/genética , Proteínas Nucleares/genética , Ribonucleoproteínas Nucleolares Pequenas/genética , Animais , Criança , Feminino , Predisposição Genética para Doença , Humanos , Longevidade , Masculino , Modelos Moleculares , Simulação de Dinâmica Molecular , Mutação , Linhagem , Conformação Proteica , RNA Ribossômico/genética , Peixe-ZebraRESUMO
Sufficient hearing is the cornerstone of the development of children's complex sensory perception, sound recognition, speech development and optimal communication skills. Hearing screening of newborns is necessary to detect congenital hearing disorders. Compulsory objective hearing screening in Hungary is a significant improvement in early diagnosis. The Audiological Department of Otorhinolaryngology, Head and Neck Surgery Clinic at Semmelweis University serves as a verification center for children identified via the compulsory objective newborn hearing screening and necessitates more detailed assessment. The goal of this study was to summarize the verification results of the year 2018. Case history, ENT examination, electric response measurement, impedance tests, otoacoustic emission measurement, surdopedagogical examination, and genetic examination are the basics of the diagnosis and the therapy as well. Altogether 261 newborns were examined in 2018 and 164 were subjected to audiological tests during the analyzed seven-month period. Normal hearing was detected in both ears in 77% of the cases, while hearing loss has been verified in 37 patients (23% of cases). Permanent hearing loss has been diagnosed in 19 cases, 4 unilateral and 15 bilateral. Hearing loss of sensorineural origin was confirmed in 17, conductive in 2 children. Temporary hearing loss caused by otitis media with effusion was found in further 18 children which healed spontaneously in most cases. Organized neonatal objective hearing examination has been established in Hungary in 2015. As a result, we can diagnose and provide care for children with hearing loss at the earliest stage. The National Newborn Hearing Screening Registry ensures a well-coordinated and smooth process. Orv Hetil. 2019; 160(47): 1850-1855.