N-terminal deletion of specific phosphorylation sites on PHOX2B disrupts the formation of enteric neurons in vivo

2021 ◽  
Author(s):  
David F. Chang ◽  
Elizabeth A. Gilliam ◽  
Laura-Marie A. Nucho ◽  
Jazmin Garcia ◽  
Yevheniya Shevchenko ◽  
...  
Keyword(s):  
Rare Condition ◽  
Enteric Neurons ◽  
In Vivo Model ◽  
Autonomic Dysregulation ◽  
Phox2b Gene ◽  
Enteric Neuropathy ◽  
Exon 1 ◽  
Central Hypoventilation ◽  
Hypoventilation Syndrome

Mutations in the paired-like homeobox 2b (PHOX2B) gene are associated with congenital central hypoventilation syndrome (CCHS), which is a rare condition in which both autonomic dysregulation with hypoventilation and an enteric neuropathy may occur. The majority of CCHS patients have a polyalanine repeat mutation (PARM) in PHOX2B, but a minority of patients have non-polyalanine repeat mutations (NPARM), some of which have been localized to exon 1. A PHOX2B-Y14X nonsense mutation previously generated in a human pluripotent stem cell (hPSC) line results in an N-terminus truncated product missing the first 17 or 20 amino acids, possibly due to translational reinitiation at an alternate ATG start site. This N-terminal truncation in the PHOX2B protein results in the loss of two key phosphorylation residues. Though the deletion does not affect the potential for PHOX2BY14X/Y14Xmutant hPSC to differentiate into enteric neural crest cells (ENCC) in culture, it impedes in vivo development of neurons in an in vivo model of human aganglionic small intestine.

scholarly journals Congenital central hypoventilation syndrome and the PHOX2B gene: A model of respiratory and autonomic dysregulation

2010 ◽  
Vol 173 (3) ◽  
pp. 322-335 ◽  
Author(s):  
Pallavi P. Patwari ◽  
Michael S. Carroll ◽  
Casey M. Rand ◽  
Rajesh Kumar ◽  
Ronald Harper ◽  
...  
Keyword(s):  
Congenital Central Hypoventilation Syndrome ◽  
Autonomic Dysregulation ◽  
Phox2b Gene ◽  
Central Hypoventilation ◽  
Hypoventilation Syndrome

Congenital Central Hypoventilation Syndrome and the PHOX2B Gene Mutation

2011 ◽  
Vol 30 (6) ◽  
pp. 397-401 ◽  
Author(s):  
Tara L. Marion ◽  
Wanda T. Bradshaw
Keyword(s):  
Genetic Screening ◽  
Autosomal Dominant ◽  
Genetic Mutations ◽  
Congenital Central Hypoventilation Syndrome ◽  
Autonomic Dysregulation ◽  
Phox2b Gene ◽  
Dominant Disease ◽  
Neural Crest Origin ◽  
Central Hypoventilation ◽  
Hypoventilation Syndrome

Congenital central hypoventilation syndrome (CCHS) is a rare syndrome of dysfunction of the autonomic nervous system characterized by a decreased response to hypercarbia. It is a disorder in which affected individuals fail to breathe during sleep despite progressive hypercapnia and hypoxia. Infants simply fall asleep and quit breathing. They are found by their parents or caregivers blue and lifeless. CCHS is an autosomal dominant disease. It has been linked with tumors of neural crest origin, segmental aganglionosis of the colon, and diffuse autonomic dysregulation but can occur alone. Discovery of the genetic link between the paired-like homeobox 2B (PHOX2B) genetic mutations and CCHS represents a breakthrough in the diagnosis of CCHS, association of mutated alleles with disease severity, and clues to the pathophysiology responsible for the disorder. Early genetic screening and intervention can provide the families of these infants with hope for achieving a normal life.

scholarly journals Congenital Central Hypoventilation Syndrome: A Comprehensive Review and Future Challenges

2014 ◽  
Vol 2014 ◽  
pp. 1-8
Author(s):  
Karin Ljubič ◽  
Iztok Fister ◽  
Iztok Fister
Keyword(s):  
Ventilatory Support ◽  
Congenital Central Hypoventilation Syndrome ◽  
Phox2b Gene ◽  
Central Controller ◽  
Future Challenges ◽  
The Central Nervous System ◽  
Central Hypoventilation ◽  
Hypoventilation Syndrome ◽  
Cardiovascular Functions

Congenital central hypoventilation syndrome is a disorder predisposed by a paired-like homebox PHOX2B gene. A mutation in the PHOX2B gene is a requisite when diagnosing congenital central hypoventilation syndrome. This mutation is identified in 93–100% of diagnosed patients. The mutation regarding this disorder affects the sensors, the central controller, and the integration of the signals within the central nervous system. This, inter alia, leads to insufficient ventilation and a decrease in PaO2, as well as an increase in PaCO2. Affected children are at risk during and after the neonatal period. They suffer from hypoventilation periods which may be present whilst sleeping only or in more severe cases when both asleep and awake. It is important for clinicians to perform an early diagnosis of congenital central hypoventilation in order to prevent the deleterious effects of hypoxaemia, hypercapnia, and acidosis on the neurocognitive and cardiovascular functions. Patients need long-term management and appropriate ventilatory support for improving the qualities of their lives. This paper provides a detailed review of congenital central hypoventilation syndrome, a congenital disorder that is genetic in origin. We describe the genetic basis, the wider clinical picture, and those challenges during the diagnosis and management of patients with this condition.

scholarly journals A Case of Congenital Central Hypoventilation Syndrome with PHOX2B Gene Mutation in a Korean Neonate

2010 ◽  
Vol 25 (8) ◽  
pp. 1237 ◽  
Author(s):  
Kyoung-Ah Kwon ◽  
Su-Eun Park ◽  
Shin-Yun Byun ◽  
Shine-Young Kim ◽  
Sang-Hyoun Hwang
Keyword(s):  
Gene Mutation ◽  
Congenital Central Hypoventilation Syndrome ◽  
Phox2b Gene ◽  
Central Hypoventilation ◽  
Hypoventilation Syndrome

Haddad Syndrome: A Case Study

2005 ◽  
Vol 24 (4) ◽  
pp. 41-44 ◽  
Author(s):  
Lisa Shuman ◽  
Diane Youmans
Keyword(s):  
Rare Condition ◽  
Alveolar Ventilation ◽  
Congenital Central Hypoventilation Syndrome ◽  
Newborn Period ◽  
Neural Crest Development ◽  
Common Etiology ◽  
Central Hypoventilation ◽  
Hypoventilation Syndrome ◽  
Haddad Syndrome

Hirschsprung’s disease (HD), also known as congenital aganglionic megacolon, is a relatively common cause of congenital obstruction of the colon. Congenital central hypoventilation syndrome (CCHS), also known as Ondine’s curse, is a rare condition involving failed autonomic respiration in the absence of cardiorespiratory disease resulting in inadequate alveolar ventilation. Both conditions typically present in the newborn period and belong to a group of disorders referred to as neurocristopathies.HD and CCHS most commonly exist as discrete entities, but the coexistence of them is now called Haddad syndrome. Although few documented cases of Haddad syndrome exist in the literature, the association of CCHS and HD suggests a common etiology involving neural crest development.

Congenital Central Hypoventilation Syndrome with PHOX2B Gene Mutation: Are We Missing the Diagnosis?

2012 ◽  
Vol 80 (8) ◽  
pp. 688-690 ◽  
Author(s):  
Nilay Nirupam ◽  
Rajni Sharma ◽  
Viswas Chhapola ◽  
Sandeep Kumar Kanwal ◽  
Elizabeth M. Berry-Kravis ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Congenital Central Hypoventilation Syndrome ◽  
Phox2b Gene ◽  
Central Hypoventilation ◽  
Hypoventilation Syndrome
Sign in / Sign up

Export Citation Format

Share Document