1. Homozygous loss-of-function mutations in SLC26A7 cause goitrous congenital hypothyroidism
- Author
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Cangul, Hakan, Liao, Xiao-Hui, Schoenmakers, Erik, Kero, Jukka, Barone, Sharon, Srichomkwun, Panudda, Iwayama, Hideyuki, Serra, Eva G, Saglam, Halil, Eren, Erdal, Tarim, Omer, Nicholas, Adeline K, Zvetkova, Ilona, Anderson, Carl A, Frankl, Fiona E Karet, Boelaert, Kristien, Ojaniemi, Marja, Jääskeläinen, Jarmo, Patyra, Konrad, Löf, Christoffer, Williams, E Dillwyn, UK10K Consortium, Soleimani, Manoocher, Barrett, Timothy, Maher, Eamonn R, Chatterjee, V Krishna, Refetoff, Samuel, Schoenmakers, Nadia, Cangul, Hakan Istanbul Medipol Univ, Dept Med Genet, Int Sch Med, Istanbul, Turkey, Liao, Xiao-Hui, Srichomkwun, Panudda, Iwayama, Hideyuki, Refetoff, Samuel Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA, Schoenmakers, Erik, Nicholas, Adeline K., Zvetkova, Ilona, Chatterjee, V. Krishna, Schoenmakers, Nadia Univ Cambridge, Metabol Res Labs, Wellcome Trust Med Res Council, Inst Metab Sci,Addenbrookes Hosp, Level 4,Box 289,Hills Rd, Cambridge CB2 0QQ, England, Kero, Jukka, Patyra, Konrad, Lof, Christoffer Univ Turku, Res Ctr Integrat Physiol & Pharmacol, Inst Biomed, Turku, Finland, Kero, Jukka Turku Univ Hosp, Dept Paediat, Turku, Finland, Barone, Sharon, Soleimani, Manoocher Univ Cincinnati, Cincinnati, OH USA, Soleimani, Manoocher Vet Adm Hosp, Cincinnati, OH USA, Serra, Eva G., Anderson, Carl A. Wellcome Trust Sanger Inst, Dept Human Genet, Cambridge, England, Saglam, Halil, Eren, Erdal, Tarim, Omer Uludag Univ, Sch Med, Dept Paediat Endocrinol, Bursa, Turkey, Frankl, Fiona E. Karet Univ Cambridge, Dept Med Genet, Cambridge, England, Frankl, Fiona E. Karet Univ Cambridge, Div Renal Med, Cambridge, England, Boelaert, Kristien Univ Birmingham, Inst Metab & Syst Res, Birmingham, W Midlands, England, Boelaert, Kristien Birmingham Hlth Partners, Ctr Endocrinol Diabet & Metab, Birmingham, W Midlands, England, Ojaniemi, Marja Univ Oulu, PEDEGO Res Ctr, Oulu, Finland, Ojaniemi, Marja Univ Oulu, MRC Oulu, Oulu, Finland, Ojaniemi, Marja Oulu Univ Hosp, Dept Children & Adolescents, Oulu, Finland, Jaaskelainen, Jarmo Univ Eastern Finland, Dept Pediat, Kuopio, Finland, Jaaskelainen, Jarmo Kuopio Univ Hosp, Kuopio, Finland, Williams, E. Dillwyn Univ Cambridge, Thyroid Carcinogenesis Grp, Strangeways Res Lab, Cambridge, England, Consortium, Ukk Univ Birmingham, Consortium Detailed Supplemental Acknowledgments, Birmingham, W Midlands, England, Barrett, Timothy Univ Birmingham, Inst Canc & Genom Sci, Coll Med & Dent Sci, Birmingham, W Midlands, England, Barrett, Timothy Birmingham Childrens Hosp, Dept Endocrinol, Birmingham, W Midlands, England, Maher, Eamonn R. Univ Cambridge, Dept Med Genet, Cambridge, England, Maher, Eamonn R. NIHR Cambridge Biomed Res Ctr, Cambridge, England, Refetoff, Samuel Univ Chicago, Dept Pediat, Chicago, IL 60637 USA, Refetoff, Samuel Univ Chicago, Comm Genet, Chicago, IL USA, Barrett, Timothy -- 0000-0002-6873-0750, MAHER, EAMONN R -- 0000-0002-6226-6918, Schoenmakers, Nadia -- 0000-0002-0847-2884, Eren, Erdal -- 0000-0002-1684-1053, Kelly, Kirsten -- 0000-0003-4234-543X, kero, jukka -- 0000-0001-8767-7222, Anderson, Carl -- 0000-0003-1719-7009, Schoenmakers, Erik [0000-0003-0674-8282], Karet, Fiona [0000-0002-2457-2869], Maher, Eamonn [0000-0002-6226-6918], Chatterjee, Krishna [0000-0002-2654-8854], Schoenmakers, Nadia [0000-0002-0847-2884], and Apollo - University of Cambridge Repository
- Subjects
Adult ,Male ,endocrine system ,endocrine system diseases ,DNA Mutational Analysis ,Thyroid Gland ,Antiporters ,Vestibular Aqueduct ,Monogenic diseases ,Mice ,Endocrinology ,Exome Sequencing ,Genetics ,Congenital Hypothyroidism ,otorhinolaryngologic diseases ,Animals ,Humans ,Molecular genetics ,Hearing Loss ,Child ,Mice, Knockout ,Goiter ,Homozygote ,Middle Aged ,Thyroid disease ,Pedigree ,HEK293 Cells ,Codon, Nonsense ,Sulfate Transporters ,FOS: Biological sciences ,Child, Preschool ,Female ,Aqueduct EVA - Abstract
WOS: 000447709700003 PubMed ID: 30333321 Defects in genes mediating thyroid hormone biosynthesis result in dyshormonogenic congenital hypothyroidism (CH). Here, we report homozygous truncating mutations in SLC26A7 in 6 unrelated families with goitrous CH and show that goitrous hypothyroidism also occurs in Slc26a7-null mice. In both species, the gene is expressed predominantly in the thyroid gland, and loss of function is associated with impaired availability of iodine for thyroid hormone synthesis, partially corrected in mice by iodine supplementation. SLC26A7 is a member of the same transporter family as SLC26A4 (pendrin), an anion exchanger with affinity for iodide and chloride (among others), whose gene mutations cause congenital deafness and dyshormonogenic goiter. However, in contrast to pendrin, SLC26A7 does not mediate cellular iodide efflux and hearing in affected individuals is normal. We delineate a hitherto unrecognized role for SLC26A7 in thyroid hormone biosynthesis, for which the mechanism remains unclear. Wellcome Trust; NIDDK NIH HHS [R37 DK015070, R01 DK015070]; Medical Research Council [MC_UU_12012/5, G0600717, G0502115]
- Published
- 2018