Cystic Fibrosis Transmembrane Conductance Regulator Protein (CFTR) Expression in the Developing Human Brain

Abstract

SummaryCystic Fibrosis Transmembrane conductance Regulator (CFTR) protein has recently been shown to be expressed in the human adult central nervous system (CNS). As CFTR expression has also been documented during embryonic development in several organs, such as the respiratory tract, the intestine and the male reproductive system, suggesting a possible role during development we decided to investigate the expression of CFTR in the human developing CNS. In addition, as some, although rare, neurological symptoms have been reported in patients with CF, we compared the expression of normal and mutated CFTR at several fetal stages. Immunohistochemistry was performed on brain and spinal cord samples of foetuses between 13 and 40 weeks of gestation and compared with five patients with cystic fibrosis (CF) of similar ages. We showed in this study that CFTR is only expressed in neurons and has an early and widespread distribution during development. Although we did not observe any cerebral abnormality in patients with CF, we observed a slight delay in the maturation of several brain structures. We also observed different expression and localization of CFTR depending on the brain structure or the cell maturation stage. Our findings, along with a literature review on the neurological phenotypes of patients with CF, suggest that this gene may play previously unsuspected roles in neuronal maturation or function. (J Histochem Cytochem 62:791-801, 2014)

A role for gene-environment interactions in Autism Spectrum Disorder is suggested by variants in genes regulating exposure to environmental factors

“…Mutations in CFTR are the main cause of cystic fibrosis, an autosomal recessive disorder characterized by mucus build-up and reduced mucociliary clearance of the respiratory tract, an important line of defense against airborne pollutants (95). CFTR is also expressed in neurons of the developing human brain (96). Other transporters found to carry relevant mutations were members of Solute Carriers (SLCs) family.…”

Autism presenting in the context of a genetic variant of CFTR and early HSV exposure confounded by chronic pain, altered gut microbiota and paternal abandonment; limitations of current pharmacotherapy and barriers to personalized treatment recommendations

“…Cystic Fibrosis (CF) is an autosomal recessive disorder resulting from more than 1900 mutations in CFTR, the gene coding for the 'Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)' located in the q31 region of chromosome 7 [3,4]. CFTR contains 1480 amino acids and functions as a cAMP-dependent Cl -, HCO 3 À , and water channel; its structure consists of 12 transmembranous domains, two nucleotide-binding domains, and a regulatory domain [3,4].…”

“…In addition to its etiological roles in classical cystic fibrosis (CF) with primary lung involvement, genetic variants of CFTR are associated with pancreatic insufficiency, dysfunction of the sweat glands, and 'congenital bilateral absence of the vas deferens (CBAVD)'. Importantly, the patient's history of a genetic variant of CFTR focuses attention on the role of this protein in development of the fetal brain; the ''ontogenetic switch" responsible for transforming GABA from an excitatory neurotransmitter into its role as the major inhibitory neurotransmitter; and a possible etiologic role of this mutant gene in ASD and other neuropsychiatric disorders [3][4][5][6]. Finally, CNS infections with HSV1 and -2 have been associated with ASD; however, the prevalence of HSV-seropositivity in ''unaffected" members of the general population is much higher than the incidence of ASD associated with HSV-exposure [7][8][9].…”

Executive functioning in pediatric cystic fibrosis: A preliminary study and conceptual model

“…Respiratory issues, such as hypoxia or hypercapnia, have been proposed as mechanisms of cognitive dysfunction in pulmonary diseases such as asthma 2,19 . The Cystic Fibrosis Transmembrane Regulator gene has also been posited as an explanation of neural symptoms in CF patients due to its expression in the central nervous system 20 . Inflammatory cytokines crossing the blood‐brain barrier and negatively impacting behavioral and emotional areas of the brain is a possibility per the neuro‐immune hypothesis 21,22 .…”