The rd3 mouse is one of the oldest identified models of early-onset retinal degeneration. Using the positional candidate approach, we have identified a C-->T substitution in a novel gene, Rd3, that encodes an evolutionarily conserved protein of 195 amino acids. The rd3 mutation results in a predicted stop codon after residue 106. This change is observed in four rd3 lines derived from the original collected mice but not in the nine wild-type mouse strains that were examined. Rd3 is preferentially expressed in the retina and exhibits increasing expression through early postnatal development. In transiently transfected COS-1 cells, the RD3-fusion protein shows subnuclear localization adjacent to promyelocytic leukemia-gene-product bodies. The truncated mutant RD3 protein is detectable in COS-1 cells but appears to get degraded rapidly. To explore potential association of the human RD3 gene at chromosome 1q32 with retinopathies, we performed a mutation screen of 881 probands from North America, India, and Europe. In addition to several alterations of uncertain significance, we identified a homozygous alteration in the invariant G nucleotide of the RD3 exon 2 donor splice site in two siblings with Leber congenital amaurosis. This mutation is predicted to result in premature truncation of the RD3 protein, segregates with the disease, and is not detected in 121 ethnically matched control individuals. We suggest that the retinopathy-associated RD3 protein is part of subnuclear protein complexes involved in diverse processes, such as transcription and splicing.

Leber congenital amaurosis (LCA) is an infantile-onset form of inherited retinal degeneration characterized by severe vision loss1, 2. Two-thirds of LCA cases are caused by mutations in 17 known disease genes3 (RetNet Retinal Information Network). Using exome sequencing, we identified a homozygous missense mutation (c.25G>A, p.Val9Met) in NMNAT1 as likely disease-causing in two siblings of a consanguineous Pakistani kindred affected by LCA. This mutation segregated with disease in their kindred, including in three other children with LCA. NMNAT1 resides in the previously identified LCA9 locus and encodes the nuclear isoform of nicotinamide mononucleotide adenylyltransferase, a rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD+) biosynthesis4, 5. Functional studies showed the p.Val9Met mutation decreased NMNAT1 enzyme activity. Sequencing NMNAT1 in 284 unrelated LCA families identified 14 rare mutations in 13 additional affected individuals. These results are the first to link an NMNAT isoform to disease and indicate that NMNAT1 mutations cause LCA.

The lattice corneal dystrophies (LCD) and granular corneal dystrophies (GCD) are autosomal dominant disorders of the corneal stroma. They are bilateral, progressive conditions characterized by the formation of opacities arising due to the deposition of insoluble material in the corneal stroma leading to visual impairment. The LCDs and GCDs are distinguished from each other and are divided into subtypes on the basis of the clinical appearance of the opacities, clinical features of the disease, and on histopathological staining properties of the deposits. The GCDs and most types of LCD arise from mutations in the transforming growth factor beta-induced (TGFBI) gene on chromosome 5q31. Over 30 mutations causing LCD and GCD have been identified so far in the TGFBI. There are two mutation hotspots corresponding to arginine residues at positions 124 and 555 of the transforming growth factor beta induced protein (TGFBIp) and they are the most frequent sites of mutation in various populations. Mutations at either of these two hotspots result in specific types of LCD or GCD. The majority of identified mutations involve residues in the fourth fasciclin-like domain of TGFBIp.

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Stevens-Johnson syndrome (SJS) and its severe variant, toxic epidermal necrolysis (TEN), are acute inflammatory vesiculobullous reactions of the skin and mucous membranes. Cold medicines including non-steroidal anti-inflammatory drugs and multi-ingredient cold medications are reported to be important inciting drugs. Recently, we reported that cold medicine related SJS/TEN (CM-SJS/TEN) with severe mucosal involvement including severe ocular surface complications (SOC) is associated with HLA-A*02:06 and HLA-B*44:03 in the Japanese. In this study, to determine whether HLA-B*44:03 is a common risk factor for CM-SJS/TEN with SOC in different ethnic groups we used samples from Indian, Brazilian, and Korean patients with CM-SJS/TEN with SOC, and investigated the association between CM-SJS/TEN with SOC and HLA-B*44:03 and/or HLA-A*02:06. We found that HLA-B*44:03 was significantly associated with CM-SJS/TEN with SOC in the Indian and Brazilian but not the Korean population, and that HLA-A*02:06 might be weakly associated in the Korean- but not the Indian and Brazilian population.

These results confirm that mutations in the SLC4A11 gene cause autosomal recessive CHED.

The cellular interleukin-6 (IL-6) gene contains a target site for the mammalian transcriptional repressor RBP. The target site is contained within the interleukin response element (ILRE), which mediates IL-6 activation by NF-kappa B. In this study, we show by using transient-expression assays that RBP represses activated transcription from the IL-6 gene. The presence and position of the RBP target site are crucial in mediating repression by RBP. While RBP binds within the ILRE, it does not target NF-kappa B alone; nonetheless, NF-kappa B binding to the ILRE is required for repression. Our results indicate that RBP represses coactivation by NF-kappa B and another cellular transcription factor, C/EBP-beta.