Idiopathic congenital central hypoventilation syndrome: Evaluation of brain‐derived neurotrophic factor genomic DNA sequence variation

Abstract

Idiopathic congenital central hypoventilation syndrome (CCHS) is an unique disorder of respiratory control, occurring in association with Hirschsprung disease (HSCR), tumors of neural crest origin, and symptoms of autonomic nervous system dysfunction (ANSD). CCHS is thought to be genetic in origin based upon 1) affected sib pairs, 2) genetic analysis, and 3) identification of genetic mutations in both HSCR and CCHS patients. Because these mutations have been found in but a few cases of CCHS, exploration of other candidate genes has continued. Brain-derived neurotrophic factor (BDNF) represents a potential candidate gene to consider because of altered respiratory control in the BDNF knock-out mouse model and localization to the enteric nervous system in human tissue. The objective of this study was to determine the frequency of BDNF mutations among 19 children with CCHS (five with HSCR) compared to 40 unaffected unrelated controls. Using the known genomic DNA sequence for BDNF, polymerase chain reaction (PCR)-amplified genomic DNA was analyzed by standard sequencing methods. A discrete mutation was identified in one of 19 children with isolated CCHS and the unaffected father. Specifically, an isoleucine was substituted for a threonine or serine in the amino acid sequence. Absence of this mutation in 40 controls confirmed that this mutation was likely not a common polymorphism. These data further support a genetic basis for CCHS, though mutations of BDNF are not consistent in this disorder.

Screening for genetic variants in BDNF that contribute to childhood obesity

“…In this study, we found the polymorphism T2I (rs8192466) in three unrelated obese individuals (frequency 0.54%). The polymorphism had previously been described in a single extremely obese boy, where the variant had been transmitted by the overweight mother and in a patient with idiopathic congenital central hypoventilation syndrome, where the proband inherited the substitution from his unaffected father and both father and son suffered from oesophageal dysmotility, gastro‐oesophageal reflux and dysphagia . Friedel et al .…”

Phylogenesis of brain-derived neurotrophic factor (BDNF)‏ in vertebrates

“…BDNF acts on neurons of the central and peripheral nervous system (Levi-Montalcini and Calissano, 1979;Leibrock et al, 1989;Purvues et al, 2001); it also rescues many sensory neurons from naturally occurring cell death (Hofer and Barde, 1988) and has been shown to be involved in the regulation of vascular development in ischemic tissues (Donovan et al, 2000;Kermani and Hempstead, 2007). Two main mutations in the BDNF protein are associated with diseases in humans: the most common is V66M, found in association with memory loss and hippocampus hyperactivation (Egan et al, 2003); the other one is L2I, which is associated with the congenital central hypoventilation syndrome, firstly described by Weese-Mayer et al (2002).…”

Novel Sequence Variations in the Brain-Derived Neurotrophic Factor Gene and Association With Major Depression and Antidepressant Treatment Response

“…Specifically, the allelic variation Thr2Ile (substitution of isoleucine for threonine at aminoacid position 2 in the coding sequence) has been implicated in the congenital central hypoventilation syndrome 23 . The variations in BDNF have been extensively studied and implicated in the susceptibility to memory and hippocampal function impairments 24 , and several psychiatric disorders 25 , such as obsessive-compulsive 26 , eating 27, 28 , bipolar 2930–34 , schizophrenia 35 , major depression 36, 37 , and Alzheimer’s disease 38–40 .…”