Functional characterization of a CDKN1B mutation in a Sardinian kindred with multiple endocrine neoplasia type 4

Pardi, Elena; Mariotti, Stefano; Pellegata, Natalia S.; Benfini, Katiuscia; Borsari, Simona; Saponaro, Federica; Torregrossa, Liborio; Cappai, A.; Satta, Chiara; Mastinu, Marco; Marcocci, Claudio; Cetani, Filomena

doi:10.1530/ec-14-0116

Cited by 36 publications

(23 citation statements)

References 32 publications

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“…In 2015, Pardi et al . characterized this germline mutation in CDKN1B c.374_375delCT (p.S125X) confirming the pathogenic role of this mutation in MEN4 (Pardi, et al 2015). Early-onset PHPT was identified in a 15-year-old girl with a germline CDKN1B variant (p.E126D) that was predicted to be damaging.…”

Section: Men4 In Humanssupporting

confidence: 54%

MEN4 and CDKN1B mutations: the latest of the MEN syndromes

Alrezk¹,

Hannah‐Shmouni²,

Stratakis³

2017

Endocrine-Related Cancer

154

104

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Multiple endocrine neoplasia (MEN) refers to a group of autosomal dominant disorders with generally high penetrance that lead to the development of a wide spectrum of endocrine and non-endocrine manifestations. The most frequent among these conditions is MEN type 1 (MEN1), which is caused by germline heterozygous loss-of-function mutations in the tumor suppressor gene MEN1. MEN1 is characterized by primary hyperparathyroidism (PHPT) and functional or nonfunctional pancreatic neuroendocrine tumors and pituitary adenomas. Approximately 10% of patients with familial or sporadic MEN1-like phenotype do not have MEN1 mutations or deletions. Recently, a novel MEN syndrome was discovered, initially in rats (MENX), and later in humans (MEN4), which is caused by germline mutations in the putative tumor suppressor CDKN1B. The most common phenotype of the 19 cases of MEN4 that have been described to date is PHPT followed by pituitary adenomas. Recently, somatic and germline mutations in CDKN1B were also identified in patients with sporadic PHPT, lymphoma, and breast cancer, demonstrating a novel role for CDKN1B as a tumor susceptibility gene for other neoplasms. In this review, we report on the genetic characterization and clinical features of MEN4.

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Section: Men4 In Humanssupporting

confidence: 54%

MEN4 and CDKN1B mutations: the latest of the MEN syndromes

Alrezk¹,

Hannah‐Shmouni²,

Stratakis³

2017

Endocrine-Related Cancer

154

104

View full text Add to dashboard Cite

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“…Multiple endocrine neoplasia type 1 MEN1 is a tumour predisposition syndrome inherited with an autosomal dominant pattern occurring with a prevalence between 1:10,000 and 1:100,000 (Pardi et al 2015). Affected individuals develop mainly parathyroid hyperplasia or parathyroid adenomas -causing primary hyperparathyroidism (in over 90% of patients by the age of 50 years) -gastroenteropancreatic neuroendocrine tumours (NETs, in approximately 60% of patients) and PAs (30-40% of cases).…”

Section: Syndromic Pituitary Tumoursmentioning

confidence: 99%

Germline and mosaic mutations causing pituitary tumours: genetic and molecular aspects

Pepe

Korbonits

Iacovazzo

2019

Journal of Endocrinology

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While 95% of pituitary adenomas arise sporadically without a known inheritable predisposing mutation, in about 5% of the cases they can arise in a familial setting, either isolated (familial isolated pituitary adenoma or FIPA) or as part of a syndrome. FIPA is caused, in 15–30% of all kindreds, by inactivating mutations in the AIP gene, encoding a co-chaperone with a vast array of interacting partners and causing most commonly growth hormone excess. While the mechanisms linking AIP with pituitary tumorigenesis have not been fully understood, they are likely to involve several pathways, including the cAMP-dependent protein kinase A pathway via defective G inhibitory protein signalling or altered interaction with phosphodiesterases. The cAMP pathway is also affected by other conditions predisposing to pituitary tumours, including X-linked acrogigantism caused by duplications of the GPR101 gene, encoding an orphan G stimulatory protein-coupled receptor. Activating mosaic mutations in the GNAS gene, coding for the Gα stimulatory protein, cause McCune–Albright syndrome, while inactivating mutations in the regulatory type 1α subunit of protein kinase A represent the most frequent genetic cause of Carney complex, a syndromic condition with multi-organ manifestations also involving the pituitary gland. In this review, we discuss the genetic and molecular aspects of isolated and syndromic familial pituitary adenomas due to germline or mosaic mutations, including those secondary to AIP and GPR101 mutations, multiple endocrine neoplasia type 1 and 4, Carney complex, McCune–Albright syndrome, DICER1 syndrome and mutations in the SDHx genes underlying the association of familial paragangliomas and phaeochromocytomas with pituitary adenomas.

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“…Studies in patients with MEN1-like tumours, but without MEN1 mutations, revealed some to have CDKN1B mutations. To date 10 different MEN4-associated mutations of CDKN1B have been reported, and the MEN4 patients have parathyroid tumours in association with pituitary adenomas and other tumours of the gonads, adrenals, thyroid and kidney ( Thakker, 2013 , Pardi et al., 2014 ).…”

Section: Pituitary Neoplasia Modelsmentioning

confidence: 99%

Animal models of pituitary neoplasia

Lines

Stevenson

Thakker

2016

Molecular and Cellular Endocrinology

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Pituitary neoplasias can occur as part of a complex inherited disorder, or more commonly as sporadic (non-familial) disease. Studies of the molecular and genetic mechanisms causing such pituitary tumours have identified dysregulation of >35 genes, with many revealed by studies in mice, rats and zebrafish. Strategies used to generate these animal models have included gene knockout, gene knockin and transgenic over-expression, as well as chemical mutagenesis and drug induction. These animal models provide an important resource for investigation of tissue-specific tumourigenic mechanisms, and evaluations of novel therapies, illustrated by studies into multiple endocrine neoplasia type 1 (MEN1), a hereditary syndrome in which ∼30% of patients develop pituitary adenomas. This review describes animal models of pituitary neoplasia that have been generated, together with some recent advances in gene editing technologies, and an illustration of the use of the Men1 mouse as a pre clinical model for evaluating novel therapies.

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Functional characterization of a CDKN1B mutation in a Sardinian kindred with multiple endocrine neoplasia type 4

Cited by 36 publications

References 32 publications

MEN4 and CDKN1B mutations: the latest of the MEN syndromes

MEN4 and CDKN1B mutations: the latest of the MEN syndromes

Germline and mosaic mutations causing pituitary tumours: genetic and molecular aspects

Animal models of pituitary neoplasia

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