Fig. 2.

Decreased outer retinal thickness on in vivo OCT screening in mice from two different pedigrees with two different mutations in Sfxn3. (A and B) Manhattan plots showing P values calculated using a recessive transmission model are shown for two Sfxn3 mutations, pew (A) and basilica (B). The −log10 P values (y-axis) are plotted vs. the chromosomal positions of the mutations (x-axis) identified in the G1 founders of each pedigree. The horizontal red line represents a threshold of P = 0.05 with Bonferroni correction. Quantitative phenotypic data (continuous variable data) from OCT measurements of BM_ELM were used for linkage analysis and show highly significant associations with the two Sfxn3 mutations. The pedigree in which the pew mutation was identified (A) contained another mutation in linkage disequilibrium with Sfxn3 (Tlx1). However, in the second pedigree (B), the only mutation with a significant association with the OCT parameter was the basilica mutation. (C and D) Normalized measurements of outer retinal thickness (BM_ELM) on OCT images of mice from a pedigree carrying the pew mutation in Sfxn3 (C) show a 50% reduction in outer retinal thickness. A similar thinning of the outer retina is seen in mice carrying the basilica mutation in Sfxn3 (D). (E) A Manhattan plot of a superpedigree that includes three pedigrees (R4889, R6650, and R6652) containing the pew or basilica allele confirms a highly significant association (P = 1.4 × 10⁻¹²⁶) of the Sfxn3 mutations and reduced outer retinal thickness. (F) The corresponding scatterplot shows a significant reduction in BM_ELM thickness in VAR (homozygous mutant) mice. Data points represent individual mice. ****P < 0.0001, Student’s t test. B6, wild-type C57BL/6J; Ref, G3 mice homozygous for the reference allele of Sfxn3; Het, G3 mice heterozygous for the mutant and reference alleles of Sfxn3; Hom, G3 mice homozygous for the mutant allele of Sfxn3.