Pacemaker channel dysfunction in a patient with sinus node disease
J. Clin. Invest. Eric Schulze-Bahr, et al. 111:1537 doi:10.1172/JCI16387 [Go to this article.]

Figure 2
Mutation detection in the HCN4 gene. (a) The human HCN4 gene consists of eight exons. The minimal exon size was 141 bp (exon 5), and the maximal size was 1,465 bp (exon 8); the largest intron was intron 1 (∼24 kb) and the smallest intron 5 (102 bp). The functional domains of the wild-type HCN4 channel are delineated below. P, pore region; 1–6, transmembrane domains. (b) Electropherogram after direct sequencing of an index patient with SND. A heterozygous 1-bp deletion (1631delC) in HCN4 resulted in a superimposing sequence pattern consisting of the wild-type and mutant exon 5 sequence. (c) The heterozygous deletion mutation induces an EciI restriction site in exon 5; after restriction enzyme analysis, the uncut wild-type fragment (380 bp) and two EciI fragments (200 and 180 bp, cut mutant fragment) were found in the index patient. Her three healthy children had the wild-type configuration. The left lane shows the size standard in base pairs (pUC19 DNA/MspI). (d) Schematic topology of HCN4 channels with six transmembrane segments (S1–S6) and intracellular N- and C-termini. Because of the reading frame shift in the nucleotide sequence, a resulting premature stop codon deleted the C-terminally located cNBD in HCN4-573X that is replaced by 29 novel amino acids (thick gray line). The relative sizes of the transmembrane segments and N- or C-termini are not drawn to scale.