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Pathogenic variations in MAML2 and MAMLD1 contribute to congenital hypothyroidism due to dyshormonogenesis by regulating the Notch signalling pathway.
Wu, Feng-Yao; Yang, Rui-Meng; Zhang, Hai-Yang; Zhan, Ming; Tu, Ping-Hui; Fang, Ya; Zhang, Cao-Xu; Song, Shi-Yang; Dong, Mei; Cui, Ren-Jie; Liu, Xiao-Yu; Yang, Liu; Yan, Chen-Yan; Sun, Feng; Zhang, Rui-Jia; Wang, Zheng; Liang, Jun; Song, Huai-Dong; Cheng, Feng; Zhao, Shuang-Xia.
Affiliation
  • Wu FY; The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Yang RM; The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Zhang HY; The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Zhan M; Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Tu PH; The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Fang Y; The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Zhang CX; The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Song SY; The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Dong M; The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Cui RJ; The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Liu XY; The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Yang L; The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Yan CY; The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Sun F; The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Zhang RJ; The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Wang Z; The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Liang J; Department of Endocrinology, The Central Hospital of Xuzhou Affiliated to Xuzhou Medical College, Xuzhou, China.
  • Song HD; The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China zhaozhao1215@126.com huaidong_s1966@163.c
  • Cheng F; Department of Laboratory Medicine, Fujian Provincial Maternity and Children's Hospital, Fuzhou, China zhaozhao1215@126.com huaidong_s1966@163.com fcheng99@126.com.
  • Zhao SX; The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China zhaozhao1215@126.com huaidong_s1966@163.c
J Med Genet ; 60(9): 874-884, 2023 09.
Article de En | MEDLINE | ID: mdl-36898841
ABSTRACT

BACKGROUND:

In several countries, thyroid dyshormonogenesis is more common than thyroid dysgenesis in patients with congenital hypothyroidism (CH). However, known pathogenic genes are limited to those directly involved in hormone biosynthesis. The aetiology and pathogenesis of thyroid dyshormonogenesis remain unknown in many patients.

METHODS:

To identify additional candidate pathogenetic genes, we performed next-generation sequencing in 538 patients with CH and then confirmed the functions of the identified genes in vitro using HEK293T and Nthy-ori 3.1 cells, and in vivo using zebrafish and mouse model organisms.

RESULTS:

We identified one pathogenic MAML2 variant and two pathogenic MAMLD1 variants that downregulated canonical Notch signalling in three patients with CH. Zebrafish and mice treated with N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butylester, a γ-secretase inhibitor exhibited clinical manifestations of hypothyroidism and thyroid dyshormonogenesis. Through organoid culture of primary mouse thyroid cells and transcriptome sequencing, we demonstrated that Notch signalling within thyroid cells directly affects thyroid hormone biosynthesis rather than follicular formation. Additionally, these three variants blocked the expression of genes associated with thyroid hormone biosynthesis, which was restored by HES1 expression. The MAML2 variant exerted a dominant-negative effect on both the canonical pathway and thyroid hormone biosynthesis. MAMLD1 also regulated hormone biosynthesis through the expression of HES3, the target gene of the non-canonical pathway.

CONCLUSIONS:

This study identified three mastermind-like family gene variants in CH and revealed that both canonical and non-canonical Notch signalling affected thyroid hormone biosynthesis.
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Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Hypothyroïdie congénitale Type d'étude: Prognostic_studies Limites: Animals / Humans Langue: En Journal: J Med Genet Année: 2023 Type de document: Article Pays d'affiliation: Chine
Texte intégral
Ajouter à My VHL
Imprimer
XML
PubMed Links
Recherche sur Google

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Hypothyroïdie congénitale Type d'étude: Prognostic_studies Limites: Animals / Humans Langue: En Journal: J Med Genet Année: 2023 Type de document: Article Pays d'affiliation: Chine