Odds-ratio for association between genotypes and traits that might be detected with a power of 0.8 at the specified minor allele frequency.

*<p>Abbreviations and definitions are given in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0002510#pone-0002510-t001" target="_blank">Table 1</a>.</p>**<p>Power was estimated assuming a log-additive genetic model, significance levels of 0.05, 0.001, and 0.00001, complete linkage disequilibrium between the single nucleotide polymorphism (SNP) studied and the genetic variant underlying the association, and the population prevalence estimates shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0002510#pone-0002510-t001" target="_blank">Table 1</a>.</p>***<p>The three significance levels, namely 0.05, 0.001, and 0.00001, refer to testing one variant, multiple variants in a single gene, and variants across the genome, respectively.</p

Density of complex ocular traits in 100 consecutive patients age 60 or older arranged by presenting diagnosis.

<p>Density of complex ocular traits in 100 consecutive patients age 60 or older arranged by presenting diagnosis.</p

STR analysis of PCR amplicons of 3 normal control (A) and 3 FECD patients (B).

<p>The bottom panel is the analysis of a FECD patient with 2 expanded alleles.</p

DNA sequence surrounding the trinucleotide repeat in the intron of the <i>TCF4</i> gene on chromosome 18.

<p>The trinucleotide repeat region is shown in red, and PCR primer sequences used for sizing the repeat region are underlined. This version of the sequence comes from the human reference sequence and contains 25 TGC repeats.</p

A comparison of TGC repeat length in TCF4 between FECD cases and normal controls.

*<p>p<0.001 for FECD cases vs. controls by Fisher's exact test.</p

Genomic Southern Blot of DNA samples from normal control (lanes 1, 4, 7 and 8) and FECD patients (lanes 2, 3, 5, 6, 9–11).

<p>Lanes 12 and 13 are laboratory control samples that have not been evaluated for FECD. Note that the samples in lanes 2, 3 and 6 are from FECD patients that do not have the repeat expansion. The samples in lanes 5, 9, and 10 are samples from FECD cases with repeat expansion over 1500 repeats. Lane L contains sizing standards.</p

Sanger DNA sequencing of DNA samples of a normal control (A) and a FECD patient with two expanded alleles (B).

<p>Sanger DNA sequencing of DNA samples of a normal control (A) and a FECD patient with two expanded alleles (B).</p

Frequency histogram of the TGC repeat length of the longest allele in all 129 samples.

<p>The length of the longest repeat in each sample is shown for both FECD patients (black bars) and normal control subjects (open bars). Note that 3 FECD patients had very long repeat expansions (more than 1500 repeats), as shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049083#pone-0049083-g004" target="_blank">Figure 4</a>.</p

Snowflake Vitreoretinal Degeneration (SVD) Mutation R162W Provides New Insights into Kir7.1 Ion Channel Structure and Function

<div><p>Snowflake Vitreoretinal Degeneration (SVD) is associated with the R162W mutation of the Kir7.1 inwardly-rectifying potassium channel. Kir7.1 is found at the apical membrane of Retinal Pigment Epithelial (RPE) cells, adjacent to the photoreceptor neurons. The SVD phenotype ranges from RPE degeneration to an abnormal b-wave to a liquid vitreous. We sought to determine how this mutation alters the structure and function of the human Kir7.1 channel. In this study, we expressed a Kir7.1 construct with the R162W mutation in CHO cells to evaluate function of the ion channel. Compared to the wild-type protein, the mutant protein exhibited a non-functional Kir channel that resulted in depolarization of the resting membrane potential. Upon co-expression with wild-type Kir7.1, R162W mutant showed a reduction of I_Kir7.1 and positive shift in ‘0’ current potential. Homology modeling based on the structure of a bacterial Kir channel protein suggested that the effect of R162W mutation is a result of loss of hydrogen bonding by the regulatory lipid binding domain of the cytoplasmic structure.</p></div

Human Kir7.1 model and Kir channel family homology within the C-linker domain.

<p>(<b>A</b>) Tetrameric structural model of Kir7.1 protein and four interacting PIP₂ molecules. The highlighted structure is enlarged for clarity of the interactions between the C-terminal hotspot and the PIP₂ head group. (<b>B</b>) R162 interacts with PIP₂ through 3 hydrogen bonds as shown by the green dotted lines. (<b>C</b>) R162W structure showing the tryptophan residue and its side chain orientation with respect to PIP₂. (<b>D</b>) Comparison of the interaction of both R and W at position 162 with PIP₂ (green dotted line), along with the adjacent K-sharing hydrogen bond (purple dotted line). (<b>E</b>) Topology of the Kir7.1 subunit showing the relative position of the C-linker and Arg (R) 162 residue located adjacent to 2nd trans-membrane domain. (<b>F)</b> The conserved basic residues amongst Kir channels are indicated by upper-case letters. Disease mutations are highlighted by bold-face letters. Residues in the C-linker region are shaded. Numbers represent the first and last residues in the corresponding sequence. The species, name and accession numbers for proteins used for this comparison were as follows: hKir1.1 NM_000220, hKir2.1 NM_010603, hKir2.2 GI: 23110982, hKir3.1 NM_002239, hKir4.1 NM_002241, hKir5.1 NM_018658, hKir7.1 NM_002242, and cKir2.2 GI: 118097849.</p