Decoding SLC26A7

Johanna Ojala; Laura Niuro; Rowmika Ravi; Vladyslav Melnyk; Veli Linnossuo; Kristiina Makkonen; Jarmo Jaaskelainen; Emmi Danner; Hanna Huopio; Harri Niinikoski; Liisa Viikari; Paivi Miettinen; Nadia Schoenmakers; Reeve Mary Pat; Jukka Kero

doi:10.1530/endoabs.101.PS3-27-06

PS3-27-06

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Endocrine Abstracts (2024) 101 PS3-27-06 | DOI: 10.1530/endoabs.101.PS3-27-06

ETA2024 Poster Presentations Thyroid and Genetics (9 abstracts)

Decoding SLC26A7’S role in congenital hypothyroidism: delayed onset, very large goiters, and thyrotropin dependent basolateral expression

Johanna Ojala ¹ , Laura Niuro ² , Rowmika Ravi ¹ , Vladyslav Melnyk ¹ , Veli Linnossuo ¹ , Kristiina Makkonen ² , Jarmo Jääskeläinen ³ , Emmi Danner ³ , Hanna Huopio ³ , Harri Niinikoski ⁴ , Liisa Viikari ⁴ , Päivi Miettinen ⁵ , Nadia Schoenmakers ⁶ , Mary Pat Reeve ⁷ & Jukka Kero ²

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¹University of Turku, Department of Clinical Sciences, Faculty of Medicine, Turku, Finland; ²University of Turku, Department of Clinical Sciences, Faculty of Medicine, and Department of Pediatrics and Adolescent Medicine, Turku, Finland; ³Kuopio University Hospital, Department of Pediatrics, Kuopio, Finland; ⁴Turku University Hospital, Department of Pediatrics and Adolescent Medicine, Turku, Finland; ⁵Hospital District of Helsinki and Uusimaa, Hospital for Children and Adolescents, Helsinki, Finland; ⁶University of Cambridge, Wellcome Trust-Mrc Institute of Metabolic Science, Cambridge, United Kingdom; ⁷University of Helsinki, Institute for Molecular Medicine Finland, Hilife, Helsinki, Finland

Background: Defects in thyroid hormone synthesis at birth lead to congenital hypothyroidism (CH). CH is usually a sporadic disease, but around 10-20% of the cases are familial, involving mutations in thyroid-specific genes. Mutations in the SLC26A7 gene have recently been linked to dyshormonogenetic goitrous CH. Ion transporter SLC26A7 is highly expressed in the thyroid, and is involved in thyroid hormone synthesis, but its function remains unclear. To gain more insight into the SLC26A7 role in thyroid function, we screened for SLC26A7 mutations in Finnish CH patients, characterized the phenotypes, and examined thyroid-specific gene expression.

Methods: A targeted next-generation exome sequencing covering all known CH causing genes was applied to the study participants with sporadic and familial CH. Expression of thyroid specific genes including SLC26A7 was analyzed in two mutation carriers and in normal, goitrous and hyperactive thyroids. Additional expression analyses were done using previously reported hypothyroidism, hyperthyroid or slc26a7-deficient mouse models. Furthermore, we screened for possible disease association with the SLC26A7 gene in the Finnish population using the FinnGen database.

Results: Four families with five patients carrying the homozygous SLC26A7 (c.1893delT, p.F631Lfs*8) mutation were identified. Among them, two homozygous cases presented very large trachea-compressing goiters requiring thyroidectomy at birth. Additionally, one homozygous mutant carrier had normal thyroid function tests at birth, but developed hypothyroidism at the age of 16 with otherwise normal development, and one heterozygous patient presented with permanent CH at birth. Immunohistochemical analysis revealed thyrocyte hypertrophy with large colloid vacuoles as pathognomonic features in SLC26A7 homozygous patients. Furthermore, basolateral SLC26A7 staining was observed in normal thyrocytes, and it was more abundant in hyperthyroid patients. In mice, abundant dietary iodine-dependent SLC26A7 staining was observed in the hyperthyroid models, with less intensive staining in WT or tshr-deficient mice. Screening of the FinnGen database revealed a few other homozygous and heterozygous cases with early-onset hypothyroidism. The SLC26A7 c.1893delT, p.F631Lfs*8 variant shows 75x enrichment in the Finnish population.

Conclusions: The phenotypes in SLC26A7 mutation carriers are varied, ranging from severe CH with very large congenital goiters to cases with delayed onset of CH. SLC26A7 shows thyrotropin and dietary iodine-dependent basolateral expression, which suggest these factors could play a role in phenotypic variation among patients with SLC26A7 mutations.