CDC73-Related Disorders: Clinical Manifestations and Case Detection in Primary Hyperparathyroidism

Tuin, Karin van der; Tops, Sophie; Adank, Muriel A.; Cobben, Jan Maarten; Hamdy, Neveen A. T.; Jongmans, Marjolijn C.J.; Menko, Fred H.; Nesselrooij, Bernadette P.M. van; Netea‐Maier, Romana T.; Oosterwijk, Jan C.; Valk, Gerlof D.; Wolffenbuttel, Bruce H. R.; Hes, Frederik J.; Morreau, Hans

doi:10.1210/jc.2017-01249

Cited by 75 publications

(89 citation statements)

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“…The CDC73 gene is a tumour suppressor gene, mutations in which have been associated with hyperparathyroidism–jaw tumour syndrome and familial hyperparathyroidism [47]. Albuminuria is associated with hyperparathyroidism, which is a complication of CKD [48], and the present findings thus suggest a plausible link between the two.…”

Section: Discussionmentioning

confidence: 57%

A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes: results from an exome-wide association study of albuminuria

et al. 2018

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Aims/hypothesisIdentifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease and end-stage renal disease, which are highly prevalent in individuals with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited, with the majority of studies focusing on common variants.MethodsWe performed an exome-wide association study to identify coding variants in a two-stage (discovery and replication) approach. Data from 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and 2605 Greenlanders were included.ResultsWe identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, β = 0.27, p = 1.3 × 10−11) associated with albuminuria as a continuous measure in the combined European meta-analysis. The presence of each rare allele of the variant was associated with a 6.4% increase in albuminuria. The rare CUBN variant had an effect that was three times stronger in individuals with type 2 diabetes compared with those without (pinteraction = 7.0 × 10−4, β with diabetes = 0.69, β without diabetes = 0.20) in the discovery meta-analysis. Gene-aggregate tests based on rare and common variants identified three additional genes associated with albuminuria (HES1, CDC73 and GRM5) after multiple testing correction (pBonferroni < 2.7 × 10−6).Conclusions/interpretationThe current study identifies a rare coding variant in the CUBN locus and other potential genes associated with albuminuria in individuals with and without diabetes. These genes have been implicated in renal and cardiovascular dysfunction. The findings provide new insights into the genetic architecture of albuminuria and highlight target genes and pathways for the prevention of diabetes-related kidney disease.Electronic supplementary materialThe online version of this article (10.1007/s00125-018-4783-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Section: Discussionmentioning

confidence: 57%

A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes: results from an exome-wide association study of albuminuria

et al. 2018

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“…HES1 gene is a transcription factor that is ubiquitously expressed in most organs, also including the kidneys, and has been documented to be involved in Notch signaling pathways that play a role in renal fibrosis 34 , glomerulosclerosis 35 , and other forms of kidney disease 34, 36 . The CDC73 gene is a tumor suppressor gene whose mutations have been associated to hyperparathyroidism-jaw syndrome and familial hyperparathyroidism 37 . Albuminuria is associated with hyperparathyroidism which is a complication of CKD 38 , and the present findings may thus suggest a plausible link between the two.…”

Section: Discussionmentioning

confidence: 99%

Exome wide association study on Albuminuria identifies a novel rare variant inCUBNand additional genes, in 33985 Europeans with and without diabetes

Ahluwalia

Schulz

Waage

et al. 2018

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Pa g e 2 Significance statement (120 words summary)Increased albuminuria is a key manifestation of major health burdens, including chronic kidney disease and/or cardiovascular disease. Although being partially heritable, there is a lack of knowledge on rare genetic variants that contribute to albuminuria. The current study describes the discovery and validation, of a new rare gene mutation (~1%) in the CUBN gene which associates with increased albuminuria. Its effect multiplies 3 folds among diabetes cases compared to nondiabetic individuals. The study further uncovers 3 additional genes modulating albuminuria levels in humans. Thus the current study findings provide new insights into the genetic architecture of albuminuria and highlight novel genes/pathways for prevention of diabetes related kidney disease. P a g e 3 AbstractIdentifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease (CKD) and end-stage renal disease which are highly prevalent in patients with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited with the majority of studies focusing on common variants.We performed an exome-wide association study to identify coding variants in a two phase (discovery and replication) approach, totaling to 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and further testing in Greenlanders (n = 2,605). We identify a P a g e 4 P a g e 6 P a g e 7 run (wherever required). Replication meta-analyses with p replication <0.05, were considered significant. Combined (EUR/EUR-GL) Meta analysesThe combined meta-analyses was firstly performed with all individuals of European ancestry (Combined EUR) followed by pooling of Greenlandic data (Combined EUR-GL).Any SNP with a) p replication < 0.05 and b) p meta_EUR/EUR-GL < 5.0 × 10 -8 was considered overall significant while those with 5.0 × 10 -5 > p meta_EUR/EUR-GL > 5.0 × 10 -8 were considered suggestive. Conditional analysesConditional analyses for novel SNPs identified in known loci (and/or in low LD, LD r2 <0.01) were performed to determine if the signal was independent (in discovery set). This was performed using the following linear model:trait ~ top identified SNP + secondary known SNP + other covariates. If the top SNP retained the association estimates and p value it was considered an independent signal. Gene Aggregate TestsGene-based multi-marker association testing for rare and common (MAF > 0.0001) variants was performed using the Meta Analyses for SNP-Set (Sequence) Kernel Association Test (MetaSKAT) R package (https://cran.r-project.org/web/packages/MetaSKAT/index.html). At the study-specific level, the gene-based analyses were performed against the null model accounting for gender and ten principal components, (using the previously described SKAT-O method) 14 generating SKAT objects individually for each cohort with complete ExomeWAS data (discovery studies + MDCS study, n studies = 6)) which were then meta-analyzed.The ...

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“…A szindrómát a MEN1-szindrómától elkülöníti az a megfigyelés, hogy CDC73-mutációk esetében a mellékpajzsmirigy-daganat rosszindulatú, míg MEN1-szindrómában a daganatok jóindula-túak. A mellékpajzsmirigy-állkapocs tumor szindróma fiatalabb életkorban jelentkezik, és a betegek gyakrabban szorulnak onkológiai kezelésre, mint MEN1-szindróma esetén [14].…”

Section: Egyéb Csírasejtes Génmutációk Szerepe Men1-hez Hasonló Kliniunclassified

Molekuláris genetikai vizsgálatok az örökletes endokrinológiai tumor szindrómák klinikai diagnosztikájában

et al. 2018

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Az örökletes endokrinológiai tumor szindrómák, vagy multiplex endokrin neoplasiák (MEN) közös jellegzetességei a különböző endokrin szervek daganatainak társulása egy betegben vagy egy családon belül. A MEN-szindrómáknak több altípusát különböztethetjük meg, amelyek közül az 1-es és a 2-es típus a leggyakoribb. Öröklődésük az autoszomális domináns jelleget követi, az érintett családokban 50%-os az átörökítés valószínűsége. A MEN-szindrómák mellett a sporadikus megjelenésű endokrin daganatok genetikai hátterében is igazolhatók a MEN-szindrómákért felelős gének eltérései, és a később MEN-szindrómásnak bizonyuló esetek zöme is sporadikus formaként kerül felismerésre. A molekuláris genetikai diagnosztika elsődleges szerepe ezekben a szindrómákban a betegségért felelős eltérés kimutatása, majd genetikai tanácsadást követően az érintett családokban genetikai szűrővizsgálatok végzése. A vizsgálat után a tünetmentes, de a mutációit hordozó egyének folyamatos klinikai nyomon követésével a daganatok morbiditásának megelőzése, csökkenése érhető el. Az utóbbi évek technológiai fejlődésével átalakult az örökletes kórképek molekuláris genetikai diagnosztikája is. Az új generációs szekvenálásnak a klinikai munkában történő elterjedésével az endokrindaganat-szindrómákban is bővült a vizsgálandó gének száma. A jelen összefoglalóban áttekint-jük az örökletes endokrin tumor szindrómák genetikai hátterét, és bemutatjuk a jelenleg is alkalmazott molekuláris biológiai vizsgálómódszereket. Orv Hetil. 2018; 159(7): 285-292.

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CDC73-Related Disorders: Clinical Manifestations and Case Detection in Primary Hyperparathyroidism

Cited by 75 publications

References 25 publications

A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes: results from an exome-wide association study of albuminuria

A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes: results from an exome-wide association study of albuminuria

Exome wide association study on Albuminuria identifies a novel rare variant inCUBNand additional genes, in 33985 Europeans with and without diabetes

Molekuláris genetikai vizsgálatok az örökletes endokrinológiai tumor szindrómák klinikai diagnosztikájában

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