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Novel mutations in SLC16A2 associated with a less severe phenotype of MCT8 deficiency.
Masnada, Silvia; Groenweg, Stefan; Saletti, Veronica; Chiapparini, Luisa; Castellotti, Barbara; Salsano, Ettore; Visser, W Edward; Tonduti, Davide.
Afiliación
  • Masnada S; Pediatric Neurology Unit, V. Buzzi Children's Hospital, Via Castelvetro 32, 20154, Milan, Italy.
  • Groenweg S; Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.
  • Saletti V; Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus MC, University Medical Center, CN, Rotterdam, The Netherlands.
  • Chiapparini L; Child Neurology Department, IRCCS Foundation C. Besta Neurological Institute, Milan, Italy.
  • Castellotti B; Neuroradiology Unit, IRCCS Foundation C. Besta Neurological Institute, Milan, Italy.
  • Salsano E; Unit of Genetics of Neurodegenerative and Metabolic Diseases, IRCCS Foundation C. Besta Neurological Institute, Milan, Italy.
  • Visser WE; Unit of Neurodegenerative and Neurometabolic Rare Diseases, IRCCS Foundation C. Besta Neurological Institute, Milan, Italy.
  • Tonduti D; Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus MC, University Medical Center, CN, Rotterdam, The Netherlands.
Metab Brain Dis ; 34(6): 1565-1575, 2019 12.
Article en En | MEDLINE | ID: mdl-31332729
Mutations in the thyroid hormone transporter MCT8 cause severe intellectual and motor disability and abnormal serum thyroid function tests, a syndrome known as MCT8 deficiency (or: Allan-Herndon-Dudley syndrome, AHDS). Although the majority of patients are unable to sit or walk independently and do not develop any speech, some are able to walk and talk in simple sentences. Here, we report on two cases with such a less severe clinical phenotype and consequent gross delay in diagnosis. Genetic analyses revealed two novel hemizygous mutations in the SLC16A2 gene resulting in a p.Thr239Pro and a p.Leu543Pro substitution in the MCT8 protein. In vitro studies in transiently transfected COS-1 and JEG-3 cells, and ex vivo studies in patient-derived fibroblasts revealed substantial residual uptake capacity of both mutant proteins (Leu543Pro > Thr239Pro), providing an explanation for the less severe clinical phenotype. Both mutations impair MCT8 protein stability and interfere with proper subcellular trafficking. In one of the patients calcifications were observed in the basal ganglia at the age of 29 years; an abnormal neuroradiological feature at this age that has been linked to untreated (congenital) hypothyroidism and neural cretinism. Our studies extend on previous work by identifying two novel pathogenic mutations in SLC16A2 gene resulting in a mild clinical phenotype.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Fenotipo / Atrofia Muscular / Transportadores de Ácidos Monocarboxílicos / Simportadores / Discapacidad Intelectual Ligada al Cromosoma X / Hipotonía Muscular / Mutación Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Adult / Child / Humans / Male Idioma: En Revista: Metab Brain Dis Asunto de la revista: CEREBRO / METABOLISMO Año: 2019 Tipo del documento: Article País de afiliación: Italia

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Fenotipo / Atrofia Muscular / Transportadores de Ácidos Monocarboxílicos / Simportadores / Discapacidad Intelectual Ligada al Cromosoma X / Hipotonía Muscular / Mutación Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Adult / Child / Humans / Male Idioma: En Revista: Metab Brain Dis Asunto de la revista: CEREBRO / METABOLISMO Año: 2019 Tipo del documento: Article País de afiliación: Italia