Homozygous loss-of-function mutations in SLC26A7 cause goitrous congenital hypothyroidism

Cangül, Hakan; Liao, Xiao-Hui; Schoenmakers, Erik; Kero, Jukka; Barone, Sharon; Srichomkwun, Panudda; Iwayama, Hideyuki; Serra, Eva; Sağlam, Hilal; Eren, Erdal; Tarım, Ömer; Nicholas, Adeline K.; Zvetkova, Ilona; Anderson, Carl A.; Karet, Fiona E.; Boelaert, Kristien; Ojaniemi, Marja; Jääskeläinen, Jarmo; Patyra, Konrad; Löf, Christoffer; Williams, E. D.; Soleimani, Manoocher; Barrett, Timothy; Maher, Eamonn R.; Chatterjee, Krishna; Refetoff, Samuel; Schoenmakers, Nadia

doi:10.1172/jci.insight.99631

Cited by 49 publications

(46 citation statements)

References 23 publications

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“…Oligogenicity may also modulate CH phenotype explaining the variable penetrance and expressivity of genetic defects observed in familial CH ( 18 , 28 , 34 , 39 , 40 ). Finally, WES and whole-genome sequencing have enabled novel genetic causes of CH to be defined, such as SLC26A7 mutations causing dyshormonogenesis, and TUBB1 and CDCA8 mutations in dysgenesis ( 4 , 41 , 42 ).…”

Section: Discussionmentioning

confidence: 99%

“…Dyshormonogenic CH may occur because of biallelic mutations in anion transporters mediating thyroidal iodide uptake or efflux (SLC5A5/NIS or SLC26A4/pendrin, respectively); SLC26A7; TPO (the thyroid peroxidase enzyme), which catalyzes organification of iodide and the formation of thyroid hormones; and thyroglobulin (TG), upon which thyroid hormone biosynthesis and storage occur. Additional causes include monoallelic and biallelic mutations in the NADPH-oxidase DUOX2, which generates thyroidal hydrogen peroxide; its accessory protein DUOXA2; and IYD, which recycles unused iodide ( 1 , 4 , 5 ). Mutations in TSHR, the G-protein–coupled receptor for thyroid-stimulating hormone (TSH) cause a spectrum of phenotypes ranging from severe thyroid hypoplasia to a normal-sized GIS, with the severity correlating with the number of mutated TSHR alleles and the degree of receptor functional impairment ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

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Genetics of Gland-in-situ or Hypoplastic Congenital Hypothyroidism in Macedonia

et al. 2020

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Neonatal screening in Macedonia detects congenital hypothyroidism (CH) with an incidence of 1 in 1,585, and more than 50% of cases exhibit a normally located gland- in-situ (GIS). Monogenic mutations causing dyshormonogenesis may underlie GIS CH; additionally, a small proportion of thyroid hypoplasia has a monogenic cause, such as TSHR and PAX8 defects. The genetic architecture of Macedonian CH cases has not previously been studied. We recruited screening-detected, non-syndromic GIS CH or thyroid hypoplasia cases ( n = 40) exhibiting a spectrum of biochemical thyroid dysfunction ranging from severe permanent to mild transient CH and including 11 familial cases. Cases were born at term, with birth weight >3,000 g , and thyroid morphologies included goiter ( n = 11), thyroid hypoplasia ( n = 6), and apparently normal-sized thyroid. A comprehensive, phenotype-driven, Sanger sequencing approach was used to identify genetic mutations underlying CH, by sequentially screening known dyshormonogenesis-associated genes and TSHR in GIS cases and TSHR and PAX8 in cases with thyroid hypoplasia. Potentially pathogenic variants were identified in 14 cases, of which four were definitively causative; we also detected digenic variants in three cases. Seventeen variants (nine novel) were identified in TPO ( n = 4), TG ( n = 3), TSHR ( n = 4), DUOX2 ( n = 4), and PAX8 ( n = 2). No mutations were detected in DUOXA2, NIS, IYD , and SLC26A7 . The relatively low mutation frequency suggests that factors other than recognized monogenic causes (oligogenic variants, environmental factors, or novel genes) may contribute to GIS CH in this region. Future non–hypothesis-driven, next-generation sequencing studies are required to confirm these findings.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetics of Gland-in-situ or Hypoplastic Congenital Hypothyroidism in Macedonia

et al. 2020

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“…Dyshormonogenic congenital hypothyroidism is caused by functional deficiency of thyroid hormone synthesis as a consequence of loss-of-function mutations in any of the genes involved in the biosynthesis of thyroid hormones [24]. Very recently, mutations in the SLC26A7 gene were associated with thyroid dyshormonogenesis [25, 26]. Patients with abnormal SLC26A7 function showed preserved I − accumulation but reduced I − organification [25]; however, the role of SLC26A7 in intrathyroidal I − metabolism physiology remains uncertain.…”

Section: I− Transport Defects Cause Dyshormonogenic Congenital Hypmentioning

confidence: 99%

Implications of Na+/I- Symporter Transport to the Plasma Membrane for Thyroid Hormonogenesis and Radioiodide Therapy

Martín

Geysels

Peyret

et al. 2018

Journal of the Endocrine Society

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Iodine is a crucial component of thyroid hormones; therefore, a key requirement for thyroid hormone biosynthesis is that iodide (I−) be actively accumulated in the thyroid follicular cell. The ability of the thyroid epithelia to concentrate I− is ultimately dependent on functional Na+/ I− symporter (NIS) expression at the plasma membrane. Underscoring the significance of NIS for thyroid physiology, loss-of-function mutations in the NIS-coding SLC5A5 gene cause an I− transport defect, resulting in dyshormonogenic congenital hypothyroidism. Moreover, I− accumulation in the thyroid cell constitutes the cornerstone for radioiodide ablation therapy for differentiated thyroid carcinoma. However, differentiated thyroid tumors often exhibit reduced (or even undetectable) I− transport compared with normal thyroid tissue, and they are diagnosed as cold nodules on thyroid scintigraphy. Paradoxically, immunohistochemistry analysis revealed that cold thyroid nodules do not express NIS or express normal, or even higher NIS levels compared with adjacent normal tissue, but NIS is frequently intracellularly retained, suggesting the presence of posttranslational abnormalities in the transport of the protein to the plasma membrane. Ultimately, a thorough comprehension of the mechanisms that regulate NIS transport to the plasma membrane would have multiple implications for radioiodide therapy, opening the possibility to identify new molecular targets to treat radioiodide-refractory thyroid tumors. Therefore, in this review, we discuss the current knowledge regarding posttranslational mechanisms that regulate NIS transport to the plasma membrane under physiological and pathological conditions affecting the thyroid follicular cell, a topic of great interest in the thyroid cancer field.

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“…The decreased expression of Slc26a7 (fourfold) in Vps34 cKO may affect entry of iodine in the thyroid. However, it should be mentioned that this alternative basolateral transporter, SLC26A7, may only play an indirect role in iodine uptake (3). In addition, expression of the main transporter, Nis, is *16-fold more important than that of Slc26a7.…”

Section: Discussionmentioning

confidence: 99%

“…Iodide from the bloodstream freely traverses the fenestrated endothelium of the thyroid capillaries and is taken up into thyrocytes through the basolaterally localized NIS, thanks to a Na + gradient generated by the Na + /K + -ATPase. An alternative basolateral transporter, SLC26A7, has been recently reported to also control iodide uptake, although its role might be indirect (3). Iodide diffuses freely within thyrocytes and is next transported across the apical membrane into the colloid space through apically localized transporters such as anoctamin or pendrin (SLC26A4).…”

Section: Introductionmentioning

confidence: 99%

Class III PI3K Vps34 Controls Thyroid Hormone Production by Regulating Thyroglobulin Iodination, Lysosomal Proteolysis, and Tissue Homeostasis

Grieco

Wang

Delcorte

et al. 2020

Thyroid

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Background: The production of thyroid hormones [triiodothyronine (T3), thyroxine (T4)] depends on the organization of the thyroid in follicles, which are lined by a monolayer of thyrocytes with strict apicobasal polarity. This polarization supports vectorial transport of thyroglobulin (Tg) for storage into, and recapture from, the colloid. It also allows selective addressing of channels, transporters, ion pumps, and enzymes to their appropriate basolateral [Na + /Isymporter (NIS), SLC26A7, and Na + /K + -ATPase] or apical membrane domain (anoctamin, SLC26A4, DUOX2, DUOXA2, and thyroperoxidase). How these actors of T3/T4 synthesis reach their final destination remains poorly understood. The PI 3-kinase isoform Vps34/PIK3C3 is now recognized as a main component in the general control of vesicular trafficking and of cell homeostasis through the regulation of endosomal trafficking and autophagy. We recently reported that conditional Vps34 inactivation in proximal tubular cells in the kidney prevents normal addressing of apical membrane proteins and causes abortive macroautophagy. Methods: Vps34 was inactivated using a Pax8-driven Cre recombinase system. The impact of Vps34 inactivation in thyrocytes was analyzed by histological, immunolocalization, and messenger RNA expression profiling. Thyroid hormone synthesis was assayed by 125 I injection and plasma analysis. Results: Vps34 conditional knockout (Vps34 cKO ) mice were born at the expected Mendelian ratio and showed normal growth until postnatal day 14 (P14), then stopped growing and died at *1 month of age. We therefore analyzed thyroid Vps34 cKO at P14. We found that loss of Vps34 in thyrocytes causes (i) disorganization of thyroid parenchyma, with abnormal thyrocyte and follicular shape and reduced PAS + colloidal spaces; (ii) severe noncompensated hypothyroidism with extremely low T4 levels (0.75 -0.62 lg/dL) and huge thyrotropin plasma levels (19,300 -10,500 mU/L); (iii) impaired 125 I organification at comparable uptake and frequent occurrence of follicles with luminal Tg but nondetectable T4-bearing Tg; (iv) intense signal in thyrocytes for the lysosomal membrane marker, LAMP-1, as well as Tg and the autophagy marker, p62, indicating defective lysosomal proteolysis; and (v) presence of macrophages in the colloidal space. Conclusions: We conclude that Vps34 is crucial for thyroid hormonogenesis, at least by controlling epithelial organization, Tg iodination as well as proteolytic T3/T4 excision in lysosomes.

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Homozygous loss-of-function mutations in SLC26A7 cause goitrous congenital hypothyroidism

Cited by 49 publications

References 23 publications

Genetics of Gland-in-situ or Hypoplastic Congenital Hypothyroidism in Macedonia

Genetics of Gland-in-situ or Hypoplastic Congenital Hypothyroidism in Macedonia

Implications of Na+/I- Symporter Transport to the Plasma Membrane for Thyroid Hormonogenesis and Radioiodide Therapy

Class III PI3K Vps34 Controls Thyroid Hormone Production by Regulating Thyroglobulin Iodination, Lysosomal Proteolysis, and Tissue Homeostasis

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