A Nonsense Mutation in the Hedgehog Receptor CDON Associated With Pituitary Stalk Interruption Syndrome

Bashamboo, Anu; Bignon‐Topalovic, Joelle; Rafiey, Hassan; Brauner, Raja

doi:10.1210/jc.2015-2995

Cited by 44 publications

(52 citation statements)

References 10 publications

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“…To explain the genetic spectrum in sporadic PSIS patients, we applied WES in 24 PSIS patients in our centre and, unexpectedly, no mutation in known PSIS-associated genes was uncovered. Previous studies reported that mice lacking HESX1, LHX, NKX2.1, RAX or TBX3, as well as HEX1/HES5 double knockout mice, failed to form a pituitary stalk (46,49,50). These data confirm that PSIS is multigenic disease.…”

Section: Genetic Variantssupporting

confidence: 78%

“…Both parents and two unaffected children had this variant in the heterozygous state and one healthy sister was wild-type (13). Bashamboo et al (46) identified a novel heterozygous nonsense mutation in the CDON gene in a familial case of PSIS without holoprosencephaly who presented with neonatal hypoglycaemia and cholestasis associated with growth hormone, thyroid-stimulating hormone and adrenocorticotrophic hormone deficiencies. The mutation was inherited from her mother who was operated in childhood for strabismus.…”

Section: Genetic Variantsmentioning

confidence: 99%

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Pituitary Stalk Interruption Syndrome: From Clinical Findings to Pathogenesis

Wang

Guo

Han

et al. 2017

J Neuroendocrinology

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Pituitary stalk interruption syndrome (PSIS) is a rare congenital defect manifesting with varying degrees of pituitary hormone deficiency. The signs and symptoms of PSIS during the neonatal period and infancy are often overlooked and therefore diagnosis is delayed. The typical manifestations of PSIS can be detected by magnetic resonance imaging. Several genes in the Wnt, Notch and Shh signalling pathways related to hypothalamic-pituitary development, such as PIT1, PROP1, LHX3/LHX4, PROKR2, OTX2, TGIF and HESX1, have been found to be associated with PSIS. Nevertheless, the aetiology in the majority of cases still remains unknown. In the present review, we provide an overview of clinical features of PSIS and summarise our current understanding of the underlying pathogenic mechanisms for this rare syndrome. Furthermore, we propose future research directions that may help our understanding of the aetiology of PSIS.

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Section: Genetic Variantssupporting

confidence: 78%

Section: Genetic Variantsmentioning

confidence: 99%

Pituitary Stalk Interruption Syndrome: From Clinical Findings to Pathogenesis

Wang

Guo

Han

et al. 2017

J Neuroendocrinology

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“…Among these mutated genes, transcriptional factor HESX1 ‐mediated repression of Wnt/β‐catenin targets is required for the normal development of anterior forebrain 24; Wnt/β‐catenin signalling promotes midbrain dopaminergic progenitor specification, proliferation and neurogenesis by up‐regulating OTX2 in progenitors 25; Notch signalling has been linked to PROP1 expression 26; GPR161 and CDON , the latest mutations found in patients with PSIS by WES recently, are regulators of Shh pathway 27, 28. Collectively, these pathways seem to be critical to pituitary development.…”

Section: Discussionmentioning

confidence: 99%

“…Pituitary stalk interruption syndrome is a rare developmental pituitary defect, and germline homozygous mutations in certain transcription factors including HESX1, LHX4, OTX2, SOX3, TGIF and PROP1 have been identified as the collective drivers for familial PSIS in several case reports [9,13,17,[19][20][21][22][23]. Among these mutated genes, transcriptional factor HESX1-mediated repression of Wnt/b-catenin targets is required for the normal development of anterior forebrain [24]; Wnt/b-catenin signalling promotes midbrain dopaminergic progenitor specification, proliferation and neurogenesis by up-regulating OTX2 in progenitors [25]; Notch signalling has been linked to PROP1 expression [26]; GPR161 and CDON, the latest mutations found in patients with PSIS by WES recently, are regulators of Shh pathway [27,28]. Collectively, these pathways seem to be critical to pituitary development.…”

Section: Discussionmentioning

confidence: 99%

Multi‐genic pattern found in rare type of hypopituitarism: a whole‐exome sequencing study of Han Chinese with pituitary stalk interruption syndrome

Guo

Wang

et al. 2017

J Cellular Molecular Medi

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Pituitary stalk interruption syndrome (PSIS) is a rare type of hypopituitarism manifesting various degrees of pituitary hormone deficiency. Although mutations have been identified in some familial cases, the underpinning mechanisms of sporadic patients with PSIS who are in a vast majority remain elusive, necessitating a comprehensive study using systemic approaches. We postulate that other genetic mechanisms may be responsible for the sporadic PSIS. To test this hypothesis, we conducted a study in 24 patients with PSIS of Han Chinese with no family history using whole‐exome sequencing (WES) and bioinformatic analysis. We identified a group of heterozygous mutations in 92% (22 of 24) of the patients, and these genes are mostly associated with Notch, Shh, Wnt signalling pathways. Importantly, 83% (20 of 24) of the patients had more than one mutation in those pathways suggesting synergy of compound mutations underpin the pathogenesis of sporadic PSIS.

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“…Interestingly, the mother, who was also carrying the mutation, had been operated on in childhood for strabismus. As this variant was absent from control databases, the authors concluded that it was likely responsible for the phenotype (26).…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency

Castinetti¹,

Reynaud²,

Saveanu³

et al. 2016

European Journal of Endocrinology

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Over the last 5 years, new actors involved in the pathogenesis of combined pituitary hormone deficiency in humans have been reported: they included a member of the immunoglobulin superfamily glycoprotein and ciliary G protein-coupled receptors, as well as new transcription factors and signalling molecules. New modes of inheritance for alterations of genes encoding transcription factors have also been described. Finally, actors known to be involved in a very specific phenotype (hypogonadotroph hypogonadism for instance) have been identified in a wider range of phenotypes. These data thus suggest that new mechanisms could explain the low rate of aetiological identification in this heterogeneous group of diseases. Taking into account the fact that several reviews have been published in recent years on classical aetiologies of CPHD such as mutations of POU1F1 or PROP1, we focused the present overview on the data published in the last 5 years, to provide the reader with an updated review on this rapidly evolving field of knowledge.

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A Nonsense Mutation in the Hedgehog Receptor CDON Associated With Pituitary Stalk Interruption Syndrome

Abstract: We report for the first time a mutation in the CDON gene associated with PSIS.

Cited by 44 publications

References 10 publications

Pituitary Stalk Interruption Syndrome: From Clinical Findings to Pathogenesis

Pituitary Stalk Interruption Syndrome: From Clinical Findings to Pathogenesis

Multi‐genic pattern found in rare type of hypopituitarism: a whole‐exome sequencing study of Han Chinese with pituitary stalk interruption syndrome

MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency

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