ABCMdb

PMID: 17098482

Ameen N, Silvis M, Bradbury NA
Endocytic trafficking of CFTR in health and disease.
J Cyst Fibros. 2007 Jan;6(1):1-14. Epub 2006 Nov 13., [PubMed]

Sentences

No. Mutations Sentence Comment

671 ABCC7 p.Asn287Tyr A patient with a mutation N287Y (991A→T) was identified based on a diagnosis of elevated sweat electrolytes [70]. Login to comment 672 ABCC7 p.Asn287Tyr A patient with a mutation N287Y (991A࢐T) was identified based on a diagnosis of elevated sweat electrolytes [70]. Login to comment 674 ABCC7 p.Asn287Tyr ABCC7 p.Asn287Tyr Biosynthesis and delivery of N287Y CFTR to the cell surface is unaffected, but endocytosis of N287Y CFTR from the cell surface is markedly enhanced (~twice the rate of wild-type CFTR), resulting in a 50% reduction in steady-state levels of CFTR at the cell surface. Login to comment 675 ABCC7 p.Asn287Tyr ABCC7 p.Asn287Tyr ABCC7 p.Asn287Tyr In contrast to many mutations in CFTR, the single channel properties of N287Y CFTR and wild-type CFTR are indistinguishable arguing that disease cannot be attributed to conductance or gating defects, but rather to enhanced CFTR endocytosis. Login to comment 676 ABCC7 p.Asn287Tyr ABCC7 p.Asn287Tyr The genotype of the identified patient was ΔF508/N287Y [70]. Login to comment 677 ABCC7 p.Asn287Tyr The genotype of the identified patient was ƊF508/N287Y [70]. Login to comment 678 ABCC7 p.Asn287Tyr Such data would argue that at least 25% of wild-type CFTR activity is required to ameliorate the disease symptoms in CF patients. It is of interest to note that the N287Y mutation is a gain of function mutation and appears to generate an endocytic signal that is present within the body of the protein rather than at the termini of the protein, a location not previously identified in polytopic membrane proteins. Login to comment 679 ABCC7 p.Asn287Tyr ABCC7 p.Asn287Tyr In the broader context of molecular mechanisms underlying the pathology of human genetic diseases, the significance of the observations on N287Y CFTR lies in the recognition that mutations can reduce the expression level of a membrane protein, not only by impairing its biosynthesis or stability (or in the case of ion channels their biophysical fingerprint), but also by accelerating endocytic retrieval from the plasma membrane. Login to comment 680 ABCC7 p.Arg31Cys ABCC7 p.Asn287Tyr ABCC7 p.Arg31Leu R31C and R31L are CFTR mutations that also give rise to a mild clinical phenotype [71]. Login to comment 681 ABCC7 p.Arg31Cys ABCC7 p.Arg31Leu R31C and R31L are CFTR mutations that also give rise to a mild clinical phenotype [71]. Login to comment 683 ABCC7 p.Arg31Cys ABCC7 p.Arg31Leu Expression of R31C and R31L CFTR leads to reduced macroscopic currents compared to expression of wt CFTR; however, since single channel records were not determined it is not possible to determine whether the reduced macroscopic currents are due to endocytic defects alone, or whether there are also altered gating kinetics. Login to comment 684 ABCC7 p.Arg31Cys ABCC7 p.Arg31Leu Expression of R31C and R31L CFTR leads to reduced macroscopic currents compared to expression of wt CFTR; however, since single channel records were not determined it is not possible to determine whether the reduced macroscopic currents are due to endocytic defects alone, or whether there are also altered gating kinetics. Login to comment 836 ABCC7 p.Gly551Asp For example, there is nothing known about the trafficking of G551D CFTR, a mutation common in Scottish and Scandinavian populations. Login to comment 837 ABCC7 p.Gly551Asp For example, there is nothing known about the trafficking of G551D CFTR, a mutation common in Scottish and Scandinavian populations. Login to comment