NBCel mutations and pRTA

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Until now, 12 homozygous mutations in NBCe1 have been identified in pRTA patients associated with ocular abnormalities as shown in Figure 2 [3-11].

Figure 2. NBCe1 topology and pRTA-related mutations. Numbers in circles correspond to Q29X, R298S, S427L, T485S, G486R, R510H, W516X, L522P, N721TfsX29, A799V, R881C, and S982NfsX4. White numbers in black circles indicate mutations associated with migraine.

Figure 2. NBCe1 topology and pRTA-related mutations. Numbers in circles correspond to Q29X, R298S, S427L, T485S, G486R, R510H, W516X, L522P, N721TfsX29, A799V, R881C, and S982NfsX4. White numbers in black circles indicate mutations associated with migraine.

They include eight missense mutations R298S, S427L, T485S, G486R, R510H, L522P, A799V, and R881C, two nonsense mutations Q29X and W516X, and two frame shift mutations N721TfsX29 and S982NfsX4. Except the NBCe1A-specific mutation Q29X, which is expected to yield non-functional NBCe1A but leave both NBCe1B and NBCe1C intact [4], all the other mutations lie in the common regions of NBCe1 variants. The C-terminal mutant S982NfsX4 is expected to introduce a frameshift in exon 23 and a premature stop codon for both

NBCelA (S982NfsX4) and NBCelB (S1026NfsX4), yielding the mutant proteins with 51 fewer amino acids than the wild-type proteins. On the other hand, this mutation abolishes the translation of NBCelC, the C-terminal variant skipping exon 24 [10,18].

Topological analysis using the substituted cysteine accessibility method suggests that most of these mutations are buried in the protein complex/lipid bilayer where they perform important structural roles [38]. In particular, the amino acid substitution analysis revealed that Thr485 might reside in a special position, which seems to require the OH group side chain to maintain a normal conformation of NBCe1A. Based on homology modeling to the crystallized cytoplasmic domain structure of AE1, Arg298 in the C-terminal cytoplasmic domain of NBCe1A was also predicted to reside in a solvent-inaccessible subsurface pocket and to associate with Glu91 or Glu295 via H-bonding and charge-charge interactions [39]. This unusual continuous chain of interconnected polar residues may be essential for HCO3- transporting ability of SLC4 proteins. Parker et al. recently found that in addition to a per-molecule transport defect as previous reported [7], the NBCe1 A799V mutant has an unusual HCO3--independent conductance that, if associated with mutant NBCe1 in muscle cells, could contribute to the occurrence of hypokalemic paralysis in the affected individual [40,41].

Functional analyses using different expression systems indicate that at least 50% reduction in NBCe1A activity would be required to induce severe pRTA [3,7,9]. However, no tight relationship between the degree of NBCe1A inactivation and the severity of acidemia exits, suggesting the involvement of other factors in the etiology of pRTA. Indeed, several mutants are found to display abnormal trafficking in mammalian cells [10,42,43]. As will be discussed later, defective membrane expression of NBCe1B in astrocytes may be responsible for the occurrence of migraine [10].

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