Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology

Björnsdóttir, Gyða; Þorleifsson, Guðmar; Sulem, Patrick; Norland, Kristjan; Ferkingstad, Egil; Oddsson, Ásmundur; Zink, Florian; Lund, Sigrún H.; Nawaz, Muhammad Sulaman; Walters, G. Bragi; Skúladóttir, Ástrós; Gudjonsson, Sigurjon A.; Einarsson, Guðmundur; Halldorsson, Gisli H.; Bjarnadóttir, Valgerður S.; Sveinbjörnsson, Garðar; Helgadóttir, Anna; Gudmundsson, Larus J.; Pedersen, Ole Birger; Hansen, Thomas Folkmann; Werge, Thomas; Banasik, Karina; Troelsen, Anders; Skou, Søren Thorgaard; Thørner, Lise Wegner; Erikstrup, Christian; Nielsen, Kaspar René; Mikkelsen, Susan; Andersen, Steffen; Brunak, Søren; Burgdorf, Kristoffer Sølvsten; Hjalgrim, Henrik; Jemec, Gregor B.E.; Jennum, Poul; Johansson, Pär I.; Nielsen, Kasper; Nyegaard, Mette; Bruun, Mie Topholm; Pedersen, Ole Birger; Dinh, Khoa Manh; Sørensen, Erik; Johansson, Pär I.; Stefánsson, Hreinn; Larsen, Margit Anita Hørup; Didriksen, Maria; Sækmose, Susanne Gjørup; Zeggini, Eleftheria; Hatzikotoulas, Konstantinos; Southam, Lorraine; Gilly, Arthur; Barysenka, Andrei; Meurs, Joyce B. J. van; Boer, Cindy G.; Uitterlinden, André G.; Styrkársdóttir, Unnur; Stefánsdóttir, Lilja; Jónsson, Helgi; Ingvarsson, Þorvaldur; Esko, Tõnu; Mägi, Reedik; Teder‐Laving, Maris; Ikegawa, Shiro; Terao, Chikashi; Takuwa, Hiroshi; Meulenbelt, Ingrid; Almeida, Rodrigo Coutinho de; Kloppenburg, Margreet; Tuerlings, Margo; Slagboom, P. Eline; Nelissen, Rob R.G.H.H.; Valdes, Ana M.; Mangino, Massimo; Tsezou, Aspasia; Zengini, Eleni; Alexiadis, G; Babis, George C.; Cheah, Kathryn S.E.; Wu, Tian; Samartzis, D; Cheung, Jason Pui Yin; Sham, Pak C.; Kraft, Peter P.; Kang, Jae H.; Hveem, Kristian; Zwart, John‐Anker; Luetge, Almut; Skogholt, Anne Heidi; Johnsen, Marianne Bakke; Thomas, Laurent F.; Winsvold, Bendik Slagsvold; Gabrielsen, Maiken Elvestad; Lee, Ming Ta Michael; Zhang, Yanfei; Lietman, Steven A.; Shivakumar, Manu; Smith, George Davey; Tobias, Jonathan H.; Hartley, April; Gaunt, Tom R.; Zheng, Jie; Wilkinson, J. Mark; Steinberg, Julia; Morris, Andrew P.; Jónsdóttir, Ingileif; Björnsson, Aron Hjalti; Ólafsson, Ingvar Hákon; Ulfarsson, Elfar; Blondal, Josep; Vikingsson, Arnor; Brunak, Søren; Ostrowski, Sisse Rye; Ullum, Henrik; Þorsteinsdóttir, Unnur; Stefánsson, Kári; Guðbjartsson, Daníel F.; Thorgeirsson, Thorgeir E.; Stefánsson, Kāri

doi:10.1038/s41467-022-28167-1

Cited by 28 publications

(58 citation statements)

References 78 publications

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“…Upper tail Mendelian architecture was identified in Body Fat and no complex tail architecture was detected for Neuroticism. These results support evidence from deep sequencing studies that indicate that rare variants play a substantial role in the genetic aetiology for Sitting Height (27,28) and Heel Bone Mineral Density (29).…”

Section: Power Of Statistical Tests To Identify Complex Tail Architec...supporting

confidence: 85%

Sibling Similarity Can Reveal Key Insights Into Genetic Architecture

Souaiaia

Hoggart

et al. 2023

Preprint

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The use of siblings to infer the factors influencing complex traits has been a cornerstone of quantitative genetics. Here we utilise siblings for a novel application: the identification of genetic architecture, specifically that in individuals with extreme trait values (e.g. in the top 1%). Establishing genetic architecture in these individuals is important because they are at greatest risk of disease and are most likely to harbour rare variants of large effect due to natural selection. We develop a theoretical framework that derives expected trait distributions of siblings based on an index sibling's trait value and trait heritability. This framework is used to develop statistical tests that can infer complex genetic architecture in trait tails, distinguishing between polygenic, de novo and Mendelian tail architecture. We apply our tests to UK Biobank data here, while they can be used to infer genetic architecture in any cohort or health registry that includes siblings, without requiring genetic data. We describe how our approach has the potential to help disentangle the genetic and environmental causes of extreme trait values, to identify individuals likely to carry pathogenic variants for follow-up clinical genetic testing, and to improve the design and power of future sequencing studies to detect rare variants.

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Section: Power Of Statistical Tests To Identify Complex Tail Architec...supporting

confidence: 85%

Sibling Similarity Can Reveal Key Insights Into Genetic Architecture

Souaiaia

Hoggart

et al. 2023

Preprint

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“…In conclusion, the present work demonstrates that SLC26A1 is a major determinant of sulfate homeostasis in humans. In view of recent evidence linking sulfate homeostasis to back pain and intervertebral disc disorder ( 7 ), our study identifies SLC26A1 as a potential target for modulation of musculoskeletal health.…”

Section: Discussionmentioning

confidence: 83%

“…Recently, rare loss-of-function variants of SLC13A1 have been demonstrated to be associated with hyposulfatemia, back pain, and intervertebral disc disorder, another example of painful cartilage disease ( 7 ). It is therefore very likely that the hyposulfatemia was responsible for an otherwise unexplained perichondritis of a mechanically highly stressed joint in our patient.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, a recessively inherited form of osteochondrodysplasia in dogs has been demonstrated to be due to hyposulfatemia as a consequence of a mutation in SLC13A1 ( 8 ). Moreover, a recent genome-wide association study demonstrated that intervertebral disc disorders, a very common example of painful cartilage disease, are also associated with low plasma sulfate concentrations and rare loss-of-function variants of SLC13A1 ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

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SLC26A1 is a major determinant of sulfate homeostasis in humans

Pfau

López-Cayuqueo

Scherer

et al. 2023

Journal of Clinical Investigation

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Sulfate plays a pivotal role in numerous physiological processes in the human body, including bone and cartilage health. A role of the anion transporter SLC26A1 (Sat1) for sulfate reabsorption in the kidney is supported by the observation of hyposulfatemia and hypersulfaturia in Slc26a1 -knockout mice. The impact of SLC26A1 on sulfate homeostasis in humans remains to be defined. By combining clinical genetics, functional expression assays, and population exome analysis, we identify SLC26A1 as a sulfate transporter in humans and experimentally validate several loss-of-function alleles. Whole-exome sequencing from a patient presenting with painful perichondritis, hyposulfatemia, and renal sulfate wasting revealed a homozygous mutation in SLC26A1 , which has not been previously described to the best of our knowledge. Whole-exome data analysis of more than 5,000 individuals confirmed that rare, putatively damaging SCL26A1 variants were significantly associated with lower plasma sulfate at the population level. Functional expression assays confirmed a substantial reduction in sulfate transport for the SLC26A1 mutation of our patient, which we consider to be novel, as well as for the additional variants detected in the population study. In conclusion, combined evidence from 3 complementary approaches supports SLC26A1 activity as a major determinant of sulfate homeostasis in humans. In view of recent evidence linking sulfate homeostasis with back pain and intervertebral disc disorder, our study identifies SLC26A1 as a potential target for modulation of musculoskeletal health.

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“…We hypothesize that biallelic SLC13A1 loss‐of‐function variants are more common and may also present later in life with degenerative bone and joint disease but that mild presentations escape diagnosis unless radiological evaluation is performed in childhood. In a recent genome‐wide association study, back pain due to intervertebral disc disorders was strongly associated with heterozygous loss‐of‐function variants in SLC13A1 41 . In addition, hyposulfatemia might be a risk factor for other health issues, such as hyperandrogenism, autism, atherosclerosis, and drug‐induced hepatotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Biallelic variants in the SLC13A1 sulfate transporter gene cause hyposulfatemia with a mild spondylo‐epi‐metaphyseal dysplasia

et al. 2022

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Sulfate is the fourth most abundant anion in human plasma but is not measured in clinical practice and little is known about the consequences of sulfate deficiency.Nevertheless, sulfation plays an essential role in the modulation of numerous compounds, including proteoglycans and steroids. We report the first patient with a homozygous loss-of-function variant in the SLC13A1 gene, encoding a renal and intestinal sulfate transporter, which is essential for maintaining plasma sulfate levels.The homozygous (Arg12Ter) variant in SLC13A1 was found by exome sequencing performed in a patient with unexplained skeletal dysplasia. The main clinical features were enlargement of joints and spondylo-epi-metaphyseal radiological abnormalities in early childhood, which improved with age. In addition, autistic features were noted. We found profound hyposulfatemia due to complete loss of renal sulfate reabsorption. Cholesterol sulfate was reduced. Intravenous N-acetylcysteine administration temporarily restored plasma sulfate levels. We conclude that loss of the SLC13A1 gene leads to profound hypersulfaturia and hyposulfatemia, which is mainly associated with abnormal skeletal development, possibly predisposing to degenerative bone and joint disease. The diagnosis might be easily missed and more frequent.

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Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology

Cited by 28 publications

References 78 publications

Sibling Similarity Can Reveal Key Insights Into Genetic Architecture

Sibling Similarity Can Reveal Key Insights Into Genetic Architecture

SLC26A1 is a major determinant of sulfate homeostasis in humans

Biallelic variants in the SLC13A1 sulfate transporter gene cause hyposulfatemia with a mild spondylo‐epi‐metaphyseal dysplasia

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