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Further Insights into the Allan-Herndon-Dudley Syndrome: Clinical and Functional Characterization of a Novel MCT8 Mutation.

Armour CM, Kersseboom S, Yoon G, Visser TJ - PLoS ONE (2015)

Bottom Line: Functional analysis of the S290F mutant showed decreased TH transport, metabolism and protein expression in the three cell types, whereas the S290A mutation had no effect.However, no effect of the S290F mutation was observed on TH efflux from COS1 and JEG3 cells.Furthermore, our results indicate that the function of the S290F mutant is dependent on cell context.

View Article: PubMed Central - PubMed

Affiliation: Regional Genetics Program, Children's Hospital of Eastern Ontario, and Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.

ABSTRACT

Background: Mutations in the thyroid hormone (TH) transporter MCT8 have been identified as the cause for Allan-Herndon-Dudley Syndrome (AHDS), characterized by severe psychomotor retardation and altered TH serum levels. Here we report a novel MCT8 mutation identified in 4 generations of one family, and its functional characterization.

Methods: Proband and family members were screened for 60 genes involved in X-linked cognitive impairment and the MCT8 mutation was confirmed. Functional consequences of MCT8 mutations were studied by analysis of [125I]TH transport in fibroblasts and transiently transfected JEG3 and COS1 cells, and by subcellular localization of the transporter.

Results: The proband and a male cousin demonstrated clinical findings characteristic of AHDS. Serum analysis showed high T3, low rT3, and normal T4 and TSH levels in the proband. A MCT8 mutation (c.869C>T; p.S290F) was identified in the proband, his cousin, and several female carriers. Functional analysis of the S290F mutant showed decreased TH transport, metabolism and protein expression in the three cell types, whereas the S290A mutation had no effect. Interestingly, both uptake and efflux of T3 and T4 was impaired in fibroblasts of the proband, compared to his healthy brother. However, no effect of the S290F mutation was observed on TH efflux from COS1 and JEG3 cells. Immunocytochemistry showed plasma membrane localization of wild-type MCT8 and the S290A and S290F mutants in JEG3 cells.

Conclusions: We describe a novel MCT8 mutation (S290F) in 4 generations of a family with Allan-Herndon-Dudley Syndrome. Functional analysis demonstrates loss-of-function of the MCT8 transporter. Furthermore, our results indicate that the function of the S290F mutant is dependent on cell context. Comparison of the S290F and S290A mutants indicates that it is not the loss of Ser but its substitution with Phe, which leads to S290F dysfunction.

No MeSH data available.


Related in: MedlinePlus

Brain MRI of the index patient.T2-weighted axial images at 23 months, 3 years and 2 months showing delayed myelination, and at 10 years and 10 months myelination has normalized.
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pone.0139343.g002: Brain MRI of the index patient.T2-weighted axial images at 23 months, 3 years and 2 months showing delayed myelination, and at 10 years and 10 months myelination has normalized.

Mentions: MRI of the brain carried out at age 23 months and again at 3 years, were suggestive of delayed myelination (Fig 2) but a repeat study at 10 years was normal. Nerve conduction studies and evoked potentials were normal. Metabolic testing including plasma homocysteine, vitamin B12 level, carnitine profile, very long chain fatty acids, ammonia, plasma amino acids, urine organic acids, urine mucopolysaccharides, lactate, CK, and copper levels were normal. Testing for congenital disorders of glycosylation and disorders of neurotransmitter metabolism was also normal. Karyotype and microarray analyses were normal. Molecular genetic testing for Pelizaeus-Merzbacher Disease, Fragile X, Myotonic Dystrophy, Prader-Willi Syndrome, Spinal Muscular Atrophy and Coffin-Lowry syndrome was normal. A next generation sequencing panel of 60 genes implicated in X-linked cognitive handicap (see methods) revealed a c.C869T mutation of uncertain pathogenicity in SLC16A2.


Further Insights into the Allan-Herndon-Dudley Syndrome: Clinical and Functional Characterization of a Novel MCT8 Mutation.

Armour CM, Kersseboom S, Yoon G, Visser TJ - PLoS ONE (2015)

Brain MRI of the index patient.T2-weighted axial images at 23 months, 3 years and 2 months showing delayed myelination, and at 10 years and 10 months myelination has normalized.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4591285&req=5

pone.0139343.g002: Brain MRI of the index patient.T2-weighted axial images at 23 months, 3 years and 2 months showing delayed myelination, and at 10 years and 10 months myelination has normalized.
Mentions: MRI of the brain carried out at age 23 months and again at 3 years, were suggestive of delayed myelination (Fig 2) but a repeat study at 10 years was normal. Nerve conduction studies and evoked potentials were normal. Metabolic testing including plasma homocysteine, vitamin B12 level, carnitine profile, very long chain fatty acids, ammonia, plasma amino acids, urine organic acids, urine mucopolysaccharides, lactate, CK, and copper levels were normal. Testing for congenital disorders of glycosylation and disorders of neurotransmitter metabolism was also normal. Karyotype and microarray analyses were normal. Molecular genetic testing for Pelizaeus-Merzbacher Disease, Fragile X, Myotonic Dystrophy, Prader-Willi Syndrome, Spinal Muscular Atrophy and Coffin-Lowry syndrome was normal. A next generation sequencing panel of 60 genes implicated in X-linked cognitive handicap (see methods) revealed a c.C869T mutation of uncertain pathogenicity in SLC16A2.

Bottom Line: Functional analysis of the S290F mutant showed decreased TH transport, metabolism and protein expression in the three cell types, whereas the S290A mutation had no effect.However, no effect of the S290F mutation was observed on TH efflux from COS1 and JEG3 cells.Furthermore, our results indicate that the function of the S290F mutant is dependent on cell context.

View Article: PubMed Central - PubMed

Affiliation: Regional Genetics Program, Children's Hospital of Eastern Ontario, and Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.

ABSTRACT

Background: Mutations in the thyroid hormone (TH) transporter MCT8 have been identified as the cause for Allan-Herndon-Dudley Syndrome (AHDS), characterized by severe psychomotor retardation and altered TH serum levels. Here we report a novel MCT8 mutation identified in 4 generations of one family, and its functional characterization.

Methods: Proband and family members were screened for 60 genes involved in X-linked cognitive impairment and the MCT8 mutation was confirmed. Functional consequences of MCT8 mutations were studied by analysis of [125I]TH transport in fibroblasts and transiently transfected JEG3 and COS1 cells, and by subcellular localization of the transporter.

Results: The proband and a male cousin demonstrated clinical findings characteristic of AHDS. Serum analysis showed high T3, low rT3, and normal T4 and TSH levels in the proband. A MCT8 mutation (c.869C>T; p.S290F) was identified in the proband, his cousin, and several female carriers. Functional analysis of the S290F mutant showed decreased TH transport, metabolism and protein expression in the three cell types, whereas the S290A mutation had no effect. Interestingly, both uptake and efflux of T3 and T4 was impaired in fibroblasts of the proband, compared to his healthy brother. However, no effect of the S290F mutation was observed on TH efflux from COS1 and JEG3 cells. Immunocytochemistry showed plasma membrane localization of wild-type MCT8 and the S290A and S290F mutants in JEG3 cells.

Conclusions: We describe a novel MCT8 mutation (S290F) in 4 generations of a family with Allan-Herndon-Dudley Syndrome. Functional analysis demonstrates loss-of-function of the MCT8 transporter. Furthermore, our results indicate that the function of the S290F mutant is dependent on cell context. Comparison of the S290F and S290A mutants indicates that it is not the loss of Ser but its substitution with Phe, which leads to S290F dysfunction.

No MeSH data available.


Related in: MedlinePlus