RESUMO
Pyridine Nucleotide-Disulfide Oxidoreductase Domain 2 (PYROXD2; previously called YueF) is a mitochondrial inner membrane/matrix-residing protein and is reported to regulate mitochondrial function. The clinical importance of PYROXD2 has been unclear, and little is known of the protein's precise biological function. In the present paper, we report biallelic variants in PYROXD2 identified by genome sequencing in a patient with suspected mitochondrial disease. The child presented with acute neurological deterioration, unresponsive episodes, and extreme metabolic acidosis, and received rapid genomic testing. He died shortly after. Magnetic resonance imaging (MRI) brain imaging showed changes resembling Leigh syndrome, one of the more common childhood mitochondrial neurological diseases. Functional studies in patient fibroblasts showed a heightened sensitivity to mitochondrial metabolic stress and increased mitochondrial superoxide levels. Quantitative proteomic analysis demonstrated decreased levels of subunits of the mitochondrial respiratory chain complex I, and both the small and large subunits of the mitochondrial ribosome, suggesting a mitoribosomal defect. Our findings support the critical role of PYROXD2 in human cells, and suggest that the biallelic PYROXD2 variants are associated with mitochondrial dysfunction, and can plausibly explain the child's clinical presentation.
Assuntos
Doença de Leigh/diagnóstico por imagem , Mutação de Sentido Incorreto , Proteínas Supressoras de Tumor/genética , Evolução Fatal , Humanos , Lactente , Doença de Leigh/genética , Imageamento por Ressonância Magnética , Masculino , Proteínas Mitocondriais/metabolismo , Modelos Moleculares , Proteômica , Análise de Sequência de RNA , Proteínas Supressoras de Tumor/química , Sequenciamento Completo do GenomaAssuntos
Acne Vulgar/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Minociclina/efeitos adversos , Vasculite/induzido quimicamente , Vasculite/diagnóstico por imagem , Acne Vulgar/diagnóstico , Adolescente , Diagnóstico Diferencial , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Febre/diagnóstico , Febre/etiologia , Humanos , Imageamento por Ressonância Magnética/métodos , Minociclina/uso terapêutico , Tomografia por Emissão de Pósitrons/métodos , Fatores de Risco , Sudorese/fisiologia , Vasculite/fisiopatologia , Redução de Peso/fisiologia , Suspensão de TratamentoRESUMO
Clinical whole-exome sequencing (WES) for identification of mutations leading to Mendelian disease has been offered to the medical community since 2011. Clinically undiagnosed neurological disorders are the most frequent basis for test referral, and currently, approximately 25% of such cases are diagnosed at the molecular level. To date, there are approximately 4,000 "known" disease-associated loci, and many are associated with striking dysmorphic features, making genotype-phenotype correlations relatively straightforward. A significant fraction of cases, however, lack characteristic dysmorphism or clinical pathognomonic traits and are dependent upon molecular tests for definitive diagnoses. Further, many molecular diagnoses are guided by recent gene-disease association discoveries. Hence, there is a critical interplay between clinical testing and research leading to gene-disease association discovery. Here, we describe four probands, all of whom presented with hypotonia, intellectual disability, global developmental delay, and mildly dysmorphic facial features. Three of the four also had sleep apnea. Each was a simplex case without a remarkable family history. Using WES, we identified AHDC1 de novo truncating mutations that most likely cause this genetic syndrome.