Functional analysis of monocarboxylate transporter 8 mutations in Japanese Allan-Herndon-Dudley syndrome patients
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- Islam Mohammad Saiful
- Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Japan
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- Namba Noriyuki
- Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Japan Department of Pediatrics, Osaka Hospital, Japan Community Healthcare Organization, Osaka, Japan
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- Ohata Yasuhisa
- Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Japan The First Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University, Suita, Japan
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- Fujiwara Makoto
- Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Japan Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, Maine, USA
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- Nakano Chiho
- Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Japan The First Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University, Suita, Japan
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- Takeyari Shinji
- Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Japan
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- Miyata Kei
- Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Japan
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- Nakano Yukako
- Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Japan
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- Yamamoto Kenichi
- Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Japan Department of Statistical Genetics, Graduate School of Medicine, Osaka University, Suita, Japan
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- Nakayama Hirofumi
- Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Japan The Japan Environment and Children’s Study, Osaka Unit Center, Suita, Japan
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- Kitaoka Taichi
- Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Japan
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- Kubota Takuo
- Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Japan
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- Ozono Keiichi
- Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Japan
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抄録
<p>Monocarboxylate transporter 8 (MCT8) facilitates T3 uptake into cells. Mutations in MCT8 lead to Allan-Herndon-Dudley syndrome (AHDS), which is characterized by severe psychomotor retardation and abnormal thyroid hormone profile. Nine uncharacterized MCT8 mutations in Japanese patients with severe neurocognitive impairment and elevated serum T3 levels were studied regarding the transport of T3. Human MCT8 (hMCT8) function was studied in wild-type (WT) or mutant hMCT8-transfected human placental choriocarcinoma cells (JEG3) by visualizing the locations of the proteins in the cells, detecting specific proteins, and measuring T3 uptake. We identified 6 missense (p.Arg445Ser, p.Asp498Asn, p.Gly276Arg, p.Gly196Glu, p.Gly401Arg, and p.Gly312Arg), 2 frameshift (p.Arg355Profs*64 and p.Tyr550Serfs*17), and 1 deletion (p.Pro561del) mutation(s) in the hMCT8 gene. All patients exhibited clinical characteristics of AHDS with high free T3, low-normal free T4, and normal-elevated TSH levels. All tested mutants were expressed at the protein level, except p.Arg355Profs*64 and p.Tyr550Serfs*17, which were truncated, and were inactive in T3 uptake, excluding p.Arg445Ser and p.Pro561del mutants, compared with WT-hMCT8. Immunocytochemistry revealed plasma membrane localization of p.Arg445Ser and p.Pro561del mutants similar with WT-hMCT8. The other mutants failed to localize in significant amount(s) in the plasma membrane and instead localized in the cytoplasm. These data indicate that p.Arg445Ser and p.Pro561del mutants preserve residual function, whereas p.Asp498Asn, p.Gly276Arg, p.Gly196Glu, p.Gly401Arg, p.Gly312Arg, p.Arg355Profs*64, and p.Tyr550Serfs*17 mutants lack function. These findings suggest that the mutations in MCT8 cause loss of function by reducing protein expression, impairing trafficking of protein to plasma membrane, and disrupting substrate channel.</p>
収録刊行物
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- Endocrine Journal
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Endocrine Journal 66 (1), 19-29, 2019
一般社団法人 日本内分泌学会
