Whole exome sequencing identifies mutation of EDNRA involved in ACTH-independent macronodular adrenal hyperplasia

Zhu, Jin; Cui, Liang; Wang, Wei; Hang, Xingyi; Xu, Axiang; Yang, Suxia; Dou, Jingtao; Mu, Yiming; Zhang, Xu; Gao, Jiangping

doi:10.1007/s10689-013-9642-y

Cited by 28 publications

(21 citation statements)

References 38 publications

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“…Pan-genomic studies, especially WES, are powerful tools to advance in the understanding of the genetics of PBMAH and identify new candidate genes. Considering our first whole genome sequencing study (16) and studies reported by others using WES (43,44,45), it is likely that either each of the other genes will be implicated in a small subset of patients or that a large portion of remaining patients do not have a single monogenic disorder. Recently, another WES study from China in patients with various types of adrenocortical tumors, including PBMAH, has suggested new candidate genes.…”

Section: Perspectives In the Genetic Of Pbmahmentioning

confidence: 99%

“…In this cohort, a PBMAH presented with a mutation in the histone deacetylase 9 gene (HDAC9) (44). A variant (S420T) in the endothelin receptor type A gene (EDNRA) was identified by WES and discussed as a potential cause in two patients from the same family and one sporadic case (45). EDNRA encodes for the GPCR endothelin receptor type A, involved in cardiovascular or polycystic kidney disease.…”

Section: Perspectives In the Genetic Of Pbmahmentioning

confidence: 99%

“…EDNRA encodes for the GPCR endothelin receptor type A, involved in cardiovascular or polycystic kidney disease. Sequencing of large cohorts of patients and functional studies are needed to confirm the involvement of this gene in PBMAH (45). It is also likely that future pangenomic studies will suggest new PBMAH candidate genes.…”

Section: Perspectives In the Genetic Of Pbmahmentioning

confidence: 99%

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Genetics of primary bilateral macronodular adrenal hyperplasia: a model for early diagnosis of Cushing's syndrome?

Drougat

Espiard

Bertherat

2015

European Journal of Endocrinology

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Long-term consequences of cortisol excess are frequent despite appropriate treatment after cure of Cushing's syndrome. This might be due to diagnostic delay, often difficult to reduce in rare diseases. The identification of a genetic predisposing factor might help to improve early diagnosis by familial screening. Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. Hypercortisolism in PBMAH is most often diagnosed between the fifth and sixth decades of life. The bilateral nature of the adrenocortical tumors and the occurrence of rare clear familial forms suggest a genetic origin. Indeed, a limited subset of PBMAH can be observed as part of multiple tumors syndromes due to alterations of the APC, Menin or Fumarate Hydratase genes. Rare variants of the phosphodiesterases PDE11A have been associated with PBMAH. The recent identification of ARMC5 germline alterations in 25-50% of PBMAH patients without obvious familial history or associated tumors opens new perspectives. ARMC5 alterations follow the model of a tumor suppressor gene: a first germline inactivating mutation of this 16p located gene is followed by a somatic secondary hit on the other allele (inactivating mutation or allelic loss). Functional studies demonstrate that ARMC5 controls apoptosis and steroid synthesis. The phenotype of index cases patients with the mutation seems more severe than the one of WT index cases. However, phenotype variability within a family is often observed. This review summarizes the genetics of PBMAH, focusing on ARMC5, which offer new perspectives for early diagnosis of Cushing's syndrome.

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Section: Perspectives In the Genetic Of Pbmahmentioning

confidence: 99%

Section: Perspectives In the Genetic Of Pbmahmentioning

confidence: 99%

Section: Perspectives In the Genetic Of Pbmahmentioning

confidence: 99%

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Genetics of primary bilateral macronodular adrenal hyperplasia: a model for early diagnosis of Cushing's syndrome?

Drougat

Espiard

Bertherat

2015

European Journal of Endocrinology

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“…A single study reported a single mutation in Endothelin Receptor type A EDNRA gene, but this has not been confirmed in any other sequencing studies of large series of patients with adrenal hyperplasia. EDNRA belongs to G proteincoupled proteins and was also reported to play a role in cardiovascular and polycystic kidney disease (Zhu et al 2013). The frequency of the alterations of these genes has not been investigated in large series.…”

Section: Primary Bilateral Macronodular Adrenal Hyperplasia (Pbmah)mentioning

confidence: 99%

Genetics of tumors of the adrenal cortex

Bonnet-Serrano

Bertherat

2018

Endocrine-Related Cancer

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This review describes the molecular alterations observed in the various types of tumors of the adrenal cortex, excluding Conn adenomas, especially the alterations identified by genomic approaches these last five years. Two main forms of bilateral adrenocortical tumors can be distinguished according to size and aspect of the nodules: primary pigmented nodular adrenal disease (PPNAD), which can be sporadic or part of Carney complex and primary bilateral macro nodular adrenal hyperplasia (PBMAH). The bilateral nature of the tumors suggests the existence of an underlying genetic predisposition. PPNAD and Carney complex are mainly due to germline-inactivating mutations of PRKAR1A, coding for a regulatory subunit of PKA, whereas PBMAH genetic seems more complex. However, genome-wide approaches allowed the identification of a new tumor suppressor gene, ARMC5, whose germline alteration could be responsible for at least 25% of PBMAH cases. Unilateral adrenocortical tumors are more frequent, mostly adenomas. The Wnt/beta-catenin pathway can be activated in both benign and malignant tumors by CTNNB1 mutations and by ZNRF3 inactivation in adrenal cancer (ACC). Some other signaling pathways are more specific of the tumor dignity. Thus, somatic mutations of cAMP/PKA pathway genes, mainly PRKACA, coding for the catalytic alpha-subunit of PKA, are found in cortisol-secreting adenomas, whereas IGF-II overexpression and alterations of p53 signaling pathway are observed in ACC. Genomewide approaches including transcriptome, SNP, methylome and miRome analysis have identified new genetic and epigenetic alterations and the further clustering of ACC in subgroups associated with different prognosis, allowing the development of new prognosis markers.

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“…55 The gene endothelin receptor type A was identified as a putative gene of PBMAH by another WES study. 56 Functional studies will be important to confirm the involvement of these newly described gene alterations in the pathophysiology of PBMAH.…”

Section: Primary Bilateral Macronodular Adrenal Hyperplasiamentioning

confidence: 99%