RESUMO
The La-related protein 7 (LARP7) forms a complex with the nuclear 7SK RNA to regulate RNA polymerase II transcription. It has been implicated in cancer and the Alazami syndrome, a severe developmental disorder. Here, we report a so far unknown role of this protein in RNA modification. We show that LARP7 physically connects the spliceosomal U6 small nuclear RNA (snRNA) with a distinct subset of box C/D small nucleolar RNAs (snoRNAs) guiding U6 2'-O-methylation. Consistently, these modifications are severely compromised in the absence of LARP7. Although general splicing remains largely unaffected, transcriptome-wide analysis revealed perturbations in alternative splicing in LARP7-depleted cells. Importantly, we identified defects in 2'-O-methylation of the U6 snRNA in Alazami syndrome siblings carrying a LARP7 mutation. Our data identify LARP7 as a bridging factor for snoRNA-guided modification of the U6 snRNA and suggest that alterations in splicing fidelity contribute to the etiology of the Alazami syndrome.
Assuntos
Processamento Alternativo , Deficiências do Desenvolvimento/metabolismo , RNA Nuclear Pequeno/metabolismo , Ribonucleoproteínas/metabolismo , Spliceossomos/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Criança , Pré-Escolar , Sequência Conservada , Deficiências do Desenvolvimento/genética , Feminino , Predisposição Genética para Doença , Células HEK293 , Humanos , Masculino , Metilação , Pessoa de Meia-Idade , Mutação , Conformação de Ácido Nucleico , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , RNA Nuclear Pequeno/genética , Ribonucleoproteínas/genética , Spliceossomos/genéticaRESUMO
BACKGROUND: Mucopolysaccharidosis type III (Sanfilippo syndrome) is a lysosomal storage disorder, caused by a deficiency in the heparan-N-sulfatase enzyme involved in the catabolism of the glycosaminoglycan heparan sulfate. It is characterized by early nonspecific neuropsychiatric symptoms, followed by progressive neurocognitive impairment in combination with only mild somatic features. In this patient group with a broad clinical spectrum a significant genotype-phenotype correlation with some mutations leading to a slower progressive, attenuated course has been demonstrated. CASE PRESENTATION: Our patient had complications in the neonatal period and was diagnosed with Mucopolysaccharidosis IIIa only at the age of 28 years. He was compound heterozygous for the variants p.R245H and p.S298P, the latter having been shown to lead to a significantly milder phenotype. CONCLUSIONS: The diagnostic delay is even more prolonged in this patient population with comorbidities and a slowly progressive course of the disease.