Missense Mutation in the Alternative Splice Region of the PAX6 Gene in Eye Anomalies

SummaryThe PAX6 gene is involved in ocular morphogenesis, and PAX6 mutations have been detected in various types of ocular anomalies, including aniridia, Peters anomaly, corneal dystrophy, congenital cataract, and foveal hypoplasia. The gene encodes a transcriptional regulator that recognizes target genes through its paired-type DNA-binding domain. The paired domain is composed of two distinct DNA-binding subdomains, the N-terminal subdomain (NTS) and the C-terminal subdomain (CTS), which bind respective consensus DNA sequences. The human PAX6 gene produces two alternative splice isoforms that have the distinct structure of the paired domain. The insertion, into the NTS, of 14 additional amino acids encoded by exon 5a abolishes the DNA-binding activity of the NTS and unmasks the DNA-binding ability of the CTS. Thus, exon 5a appears to function as a molecular switch that specifies target genes. We ascertained a novel missense mutation in four pedigrees with Peters anomaly, congenital cataract, Axenfeldt anomaly, and/or foveal hypoplasia, which, to our knowledge, is the first mutation identified in the splice-variant region. A T→A transition at the 20th nucleotide position of exon 5a results in a Val→Asp (GTC→GAC) substitution at the 7th codon of the alternative splice region. Functional analyses demonstrated that the V54D mutation slightly increased NTS binding and decreased CTS transactivation activity to almost half

Severe hypothyroidism associated with the degree of edema in a patient with nephrosis

We report the pleural fluid values of thyroid hormones and their carrier proteins in a patient who suffered from nephrotic syndrome with renal insufficiency and transient hypothyroidism. The pleural effusion was transudate. The concentrations of thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin (Alb) were approximately 30-50% of the plasma. The concentrations of total triiodothyronine (TT3), total tetraiodothyronine (TT4), free triiodothyronine (FT3), and free tetraiodothyronine (FT4) were approximately 30-50% of the plasma. Hypothyroidism was associated with the degree of edema. After improving systemic edema, proteinuria remained unchanged but the patient did not require levothyroxine. We speculate that the large amount of transudation of thyroid hormones with their carrier proteins from the blood vessels to the third space (edema and pleural effusion), thereby reducing thyroid hormones in the plasma, was associated with hypothyroidism

Severe Hypothyroidism Associated with the Degree of Edema in a Patient with Nephrosis

We report the pleural fluid values of thyroid hormones and their carrier proteins in a patient who suffered from nephrotic syndrome with renal insufficiency and transient hypothyroidism. The pleural effusion was transudate. The concentrations of thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin (Alb) were approximately 30-50% of the plasma. The concentrations of total triiodothyronine (TT3), total tetraiodothyronine (TT4), free triiodothyronine (FT3), and free tetraiodothyronine (FT4) were approximately 30-50% of the plasma. Hypothyroidism was associated with the degree of edema. After improving systemic edema, proteinuria remained unchanged but the patient did not require levothyroxine. We speculate that the large amount of transudation of thyroid hormones with their carrier proteins from the blood vessels to the third space (edema and pleural effusion), thereby reducing thyroid hormones in the plasma, was associated with hypothyroidism

Analysis of phosducin as a candidate gene for retinopathies

Phosducin, a retina-expressed gene mapped to chromosome 1q25-32.1, was analyzed as a candidate gene for retinopathies. The phosducin gene was cloned and characterized, and PCR primers were designed. Eighty-three patients with various retinopathies and 45 control subjects (24 American, 21 Japanese) were analyzed for mutations in the phosducin gene by PCR, denaturing gradient gel electrophoresis (DGGE), and sequencing. A heterozygous sequence variant changing a glycine to arginine at codon 178 was found in one Usher syndrome type II (USH2) patient, while the other USH2 patients did not show any coding sequence variant. A heterozygous sequence variant changing an asparagine to lysine at codon 174 was found in a patient with a severe retinal degeneration in the category of diseases known as acute zonal occult outer retinopathy (AZOOR). Three non-coding sequence variants were found. Two of these were always present together and found in 20.8% of American and 2.4% of Japanese control subjects, reflecting a difference in population pools. In conclusion, the phosducin gene did not show mutations consistent with it being the causative gene for USH2, but its possible pathogenicity in AZOOR or other retinopathies remains an open question which may be answered by further analysis

Bietti Crystalline Corneoretinal Dystrophy Is Caused by Mutations in the Novel Gene CYP4V2

Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive retinal dystrophy characterized by multiple glistening intraretinal crystals scattered over the fundus, a characteristic degeneration of the retina, and sclerosis of the choroidal vessels, ultimately resulting in progressive night blindness and constriction of the visual field. The BCD region of chromosome 4q35.1 was refined to an interval flanked centromerically by D4S2924 by linkage and haplotype analysis; mutations were found in the novel CYP450 family member CYP4V2 in 23 of 25 unrelated patients with BCD tested. The CYP4V2 gene, transcribed from 11 exons spanning 19 kb, is expressed widely. Homology to other CYP450 proteins suggests that CYP4V2 may have a role in fatty acid and steroid metabolism, consistent with biochemical studies of patients with BCD