ARNT2 mutation causes hypopituitarism, post-natal microcephaly, visual and renal anomalies

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.

show abstract

“…As expected, both parents were heterozygous. This duplication induces a premature stop codon and nonsense mediated decay mechanisms (6).…”

Section: Novel Transcription Factorsmentioning

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

View full text Add to dashboard Cite

show abstract

“…One example of this is where the screening of hypopituitary patients for mutations in genes known to be associated with Kallman syndrome identified mutations in FGFR1, FGF8 and PROKR2 (Raivio et al 2012). Whole exome sequencing is replacing candidate gene sequencing in the identification of novel causes of genetic disease and identified loss of function mutations in ARNT2 as a cause of hypopituitarism in one family (Webb et al 2013).…”

Section: Human and Murine Mutations Affecting The Central Gh Axismentioning

confidence: 99%

60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-GH axis: the past 60 years

Murray¹,

Higham²,

Clayton³

2015

Journal of Endocrinology

View full text Add to dashboard Cite

At the time of the publication of Geoffrey Harris's monograph on 'Neural control of the pituitary gland' 60 years ago, the pituitary was recognised to produce a growth factor, and extracts administered to children with hypopituitarism could accelerate growth. Since then our understanding of the neuroendocrinology of the GH axis has included identification of the key central components of the GH axis: GH-releasing hormone and somatostatin (SST) in the 1970s and 1980s and ghrelin in the 1990s. Characterisation of the physiological control of the axis was significantly advanced by frequent blood sampling studies in the 1980s and 1990s; the pulsatile pattern of GH secretion and the factors that influenced the frequency and amplitude of the pulses have been defined. Over the same time, spontaneously occurring and targeted mutations in the GH axis in rodents combined with the recognition of genetic causes of familial hypopituitarism demonstrated the key factors controlling pituitary development. As the understanding of the control of GH secretion advanced, developments of treatments for GH axis disorders have evolved. Administration of pituitary-derived human GH was followed by the introduction of recombinant human GH in the 1980s, and, more recently, by long-acting GH preparations. For GH excess disorders, dopamine agonists were used first followed by SST analogues, and in 2005 the GH receptor blocker pegvisomant was introduced. This review will cover the evolution of these discoveries and build a picture of our current understanding of the hypothalamo-GH axis.

show abstract

“…Whole-exome sequencing now provides the opportunity to identify novel genes implicated in hypopituitarism independent of preceding animal studies. 30 To identify novel candidate genes associated with CPHD, we started out with high-quality exome-sequencing data from 30 individuals (10 patients and their unaffected parents). A filtering pipeline resulted in a first list of on average 3.8 candidate genes per patient.…”

Section: Discussionmentioning

confidence: 99%

Identification of SLC20A1 and SLC15A4 among other genes as potential risk factors for combined pituitary hormone deficiency

Simm

Griesbeck

Choukair

et al. 2018

Genetics in Medicine

View full text Add to dashboard Cite

Purpose: Combined pituitary hormone deficiency (CPHD) is characterized by a malformed or underdeveloped pituitary gland resulting in an impaired pituitary hormone secretion. Several transcription factors have been described in its etiology, but defects in known genes account for only a small proportion of cases.Methods: To identify novel genetic causes for congenital hypopituitarism, we performed exome-sequencing studies on 10 patients with CPHD and their unaffected parents. Two candidate genes were sequenced in further 200 patients. Genotype data of known hypopituitary genes are reviewed.Results: We discovered 51 likely damaging variants in 38 genes; 12 of the 51 variants represent de novo events (24%); 11 of the 38 genes (29%) were present in the E12.5/E14.5 pituitary transcriptome. Targeted sequencing of two candidate genes, SLC20A1 and SLC15A4, of the solute carrier membrane transport protein family in 200 additional patients demonstrated two further variants predicted as damaging. We also found combinations of de novo (SLC20A1/SLC15A4) and transmitted variants (GLI2/LHX3) in the same individuals, leading to the full-blown CPHD phenotype.Conclusion: These data expand the pituitary target genes repertoire for diagnostics and further functional studies. Exome sequencing has identified a combination of rare variants in different genes that might explain incomplete penetrance in CPHD.

show abstract

ARNT2 mutation causes hypopituitarism, post-natal microcephaly, visual and renal anomalies

Cited by 68 publications

References 33 publications

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

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

60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-GH axis: the past 60 years

Identification of SLC20A1 and SLC15A4 among other genes as potential risk factors for combined pituitary hormone deficiency

Contact Info

Product

Resources

About