Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency.

BACKGROUND: Lipoprotein lipase (LPL) deficiency is a serious lipid disorder of severe hypertriglyceridemia (SHTG) with chylomicronemia. A large number of variants in the LPL gene have been reported but their influence on LPL activity and SHTG has not been completely analyzed. Gaining insight into the deleterious effect of the mutations is clinically essential. METHODS: We used gene sequencing followed by in-vivo/in-vitro and in-silico tools for classification. We classified 125 rare LPL mutations in 33 subjects thought to have LPL deficiency and in 314 subjects selected for very SHTG. RESULTS: Of the 33 patients thought to have LPL deficiency, only 13 were homozygous or compound heterozygous for deleterious mutations in the LPL gene. Among the 314 very SHTG patients, 3 were compound heterozygous for pathogenic mutants. In a third group of 51,467 subjects, from a general population, carriers of common variants, Asp9Asn and Asn291Ser, were associated with mild increase in triglyceride levels (11%-35%). CONCLUSION: In total, 39% of patients clinically diagnosed as LPL deficient had 2 deleterious variants. Three patients selected for very SHTG had LPL deficiency. The deleterious mutations associated with LPL deficiency will assist in the diagnosis and selection of patients as candidates for the presently approved LPL gene therapy.

Reduced L- and M- and increased S-cone functions in an infant with thyroid hormone resistance due to mutations in the THRß2 gene.

BACKGROUND: To document an infant with a cone photoreceptor disorder associated with severe thyroid hormone resistance due to compound heterozygosity in the thyroid hormone receptor beta 2 (TRß2) encoding gene THRß2. MATERIALS AND METHODS: Cone photoreceptor function was assessed using standard electroretinography (ERG) including colored flashes. We PCR-amplified and sequenced exons 8-10 of the THRß2 gene. We cloned and sequenced a genomic segment (exons 9-10) of the THRß2 gene to confirm a compound heterozygote mutation. We investigated whether mutations in the (OPN1LW-OPN1MW) gene array were responsible for the phenotype. RESULTS: ERG testing showed a normal scotopic response and severely reduced photopic response. Spectral testing showed a small amplitude b-wave to a red flash and a larger amplitude b-wave to the blue flash. Molecular analysis revealed this child was a compound heterozygote for p.R338W and p.R429W mutations in exons 9 and 10 of the THRß2 gene. These two mutations lie within the ligand-binding domain that is known to selectively inhibit Trß2 binding as homodimers to the thyroid hormone receptor response elements (TREs). No mutations were found within the OPN1LW and OPN1MW genes or the locus control region that regulates expression of these opsin genes. CONCLUSION: We document a congenital disorder of cone function characterized by severely reduced L- and M-cone responses and increased S-cone responses caused by deleterious mutations in the THRß2 gene in thyroid resistant patients. Thyroid hormone, via TRß2, is critical for determining cone-type differentiation in humans.

The effect of hepatic lipase on coronary artery disease in humans is influenced by the underlying lipoprotein phenotype.

Increased or decreased hepatic lipase (HL) activity has been associated with coronary artery disease (CAD). This is consistent with the findings that gene variants that influence HL activity were associated with increased CAD risk in some population studies but not in others. In this review, we will explain the conditions that influence the effects of HL on CAD. Increased HL is associated with smaller and denser LDL (sdLDL) and HDL (HDL(3)) particles, while decreased HL is associated with larger and more buoyant LDL and HDL particles. The effect of HL activity on CAD risk is dependent on the underlying lipoprotein phenotype or disorder. Central obesity with hypertriglyceridemia (HTG) is associated with high HL activity that leads to the formation of sdLDL that is pro-atherogenic. In the absence of HTG, where large buoyant cholesteryl ester-enriched LDL is prominent, elevation of HL does not raise the risk for CAD. In HTG patients, drug therapy that decreases HL activity selectively decreases sdLDL particles, an anti-atherogenic effect. Drug therapy that raises HDL(2) cholesterol has not decreased the risk for CAD. In trials where inhibition of cholesterol ester transfer protein (CETP) or HL occurs, the increase in HDL(2) most likely is due to inhibition of catabolism of HDL(2) and impairment of reverse cholesterol transport (RCT). In patients with isolated hypercholesterolemia, but with normal triglyceride levels and big-buoyant LDL particles, an increase in HL activity is beneficial; possibly because it increases RCT. Drugs that lower HL activity might decrease the risk for CAD only in hypertriglyceridemic patients with sdLDL by selectively clearing sdLDL particles from plasma, which would override the potentially pro-atherogenic effect on RCT. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).

The dimensionality of color vision in carriers of anomalous trichromacy.

Some 12% of women are carriers of the mild, X-linked forms of color vision deficiencies called "anomalous trichromacy." Owing to random X chromosome inactivation, their retinae must contain four classes of cone rather than the normal three; and it has previously been speculated that these female carriers might be tetrachromatic, capable of discriminating spectral stimuli that are indistinguishable to the normal trichromat. However, the existing evidence is sparse and inconclusive. Here, we address the question using (a) a forced-choice version of the Rayleigh test, (b) a test using multidimensional scaling to reveal directly the dimensionality of the participants' color space, and (c) molecular genetic analyses to estimate the X-linked cone peak sensitivities of a selected sample of strong candidates for tetrachromacy. Our results suggest that most carriers of color anomaly do not exhibit four-dimensional color vision, and so we believe that anomalous trichromacy is unlikely to be maintained by an advantage to the carriers in discriminating colors. However, 1 of 24 obligate carriers of deuteranomaly exhibited tetrachromatic behavior on all our tests; this participant has three well-separated cone photopigments in the long-wave spectral region in addition to her short-wave cone. We assess the likelihood that behavioral tetrachromacy exists in the human population.

The role of the PGC1α Gly482Ser polymorphism in weight gain due to intensive diabetes therapy.

The Diabetes Control and Complications Trial (DCCT) involved intensive diabetes therapy of subjects with type 1 diabetes mellitus (T1DM) for an average period of 6.5 years. A subset of these subjects gained excessive weight. We tested for association of polymorphisms in 8 candidate genes with the above trait. We found the Gly482Ser polymorphism in the peroxisome proliferator-activated receptor γ coactivator-1α (PGC1α) to be significantly associated with weight gain in males (P = .0045) but not in females. The Ser allele was associated with greater weight gain than the Gly allele (P = .005). Subjects with a family history of type 2 diabetes mellitus (T2DM) were more common among those who gained excessive weight. We conclude that T2DM and the Gly482Ser polymorphism in PGC1α contribute to the effect of intensive diabetes therapy on weight gain in males with T1DM.

Cone visual pigments of monotremes: filling the phylogenetic gap.

We have determined the sequence and genomic organization of the genes encoding the cone visual pigment of the platypus (Ornithorhynchus anatinus) and the echidna (Tachyglossus aculeatus), and inferred their spectral properties and evolutionary pathways. We prepared platypus and echidna retinal RNA and used primers of the middle-wave-sensitive (MWS), long-wave-sensitive (LWS), and short-wave sensitive (SWS1) pigments corresponding to coding sequences that are highly conserved among mammals; to PCR amplify the corresponding pigment sequences. Amplification from the retinal RNA revealed the expression of LWS pigment mRNA that is homologous in sequence and spectral properties to the primate LWS visual pigments. However, we were unable to amplify the mammalian SWS1 pigment from these two species, indicating this gene was lost prior to the echidna-platypus divergence (21 MYA). Subsequently, when the platypus genome sequence became available, we found an LWS pigment gene in a conserved genomic arrangement that resembles the primate pigment, but, surprisingly we found an adjacent (20 kb) SWS2 pigment gene within this conserved genomic arrangement. We obtained the same result after sequencing the echidna genes. The encoded SWS2 pigment is predicted to have a wavelength of maximal absorption of about 440 nm, and is paralogous to SWS pigments typically found in reptiles, birds, and fish but not in mammals. This study suggests the locus control region (LCR) has played an important role in the conservation of photo receptor gene arrays and the control of their spatial and temporal expression in the retina in all mammals. In conclusion, a duplication event of an ancestral cone visual pigment gene, followed by sequence divergence and selection gave rise to the LWS and SWS2 visual pigments. So far, the echidna and platypus are the only mammals that share the gene structure of the LWS-SWS2 pigment gene complex with reptiles, birds and fishes.

Distinguishing L from M photopigment coding sequences by hybridization to novel locked nucleic acid (LNA) oligonucleotide probes.

Many attempts have been made over the years to distinguish human and primate L (long-wavelength sensitive) from M (middle-wavelength sensitive) cone photoreceptors using either immunohistochemistry or in situ hybridization. These attempts have been unsuccessful due to the very high degree of identity between the sequences of the L and M proteins and encoding mRNAs. The recent development of chemically modified oligonucleotide probes, referred to as locked nucleic acid (LNA) probes, has shown that they hybridize with much greater affinity and specificity to the target nucleic acid. This has greatly increased the potential for differentiating L from M cones by in situ hybridization. We have designed LNA oligonucleotide probes that are complementary to either the L or M coding sequences located in exon 5 of the Macaca nemestrina L and M pigment genes. We have shown that the LNA-M and LNA-L probes hybridize specifically to their respective target nucleic acid sequences in vitro. This result strongly suggests that these probes would be instrumental in rapidly distinguishing L from M cone in the entire retina, and in defining the cone mosaic during development and in adults.

Energy balance in congenital generalized lipodystrophy type I.

Congenital generalized lipodystrophy type 1 (CGL-1) is characterized by an absence of adipose tissue and decreased serum leptin levels. Low leptin levels in CGL-1 support the claim that subjects are hypermetabolic and hyperphagic. The present study examines this claim. We determined 24-hour energy expenditure (24-h EE) (kilocalories) (n = 2) and resting metabolic rate (RMR) per kilogram of lean body mass (LBM) (n = 3) in CGL-1 and in 18 healthy control subjects. The 24-h EEs of control and subjects with CGL were compared with respect to kilocalories required per day relative to kilograms of LBM and with respect to RMR relative to kilograms of LBM. Fasting leptin, adiponectin, and 24-hour ghrelin levels were also measured in subjects with CGL-1. The 24-h EE per kilogram of LBM for the subjects with CGL-1 falls on the same regression line observed for this relationship in the controls. The RMR per kilogram of LBM in subjects with CGL-1 also was similar to that in controls. Both 24-h EE and RMR were quite increased when reported per kilogram of total body weight. Subjects with CGL-1 also have decreased fasting leptin and adiponectin hormone levels and no premeal ghrelin rise. People with CGL-1 have similar RMR and daily caloric requirements as healthy controls when these parameters are expressed as a function of LBM. Appetite-regulating hormone levels in CGL-1 suggest that multiple factors act to control appetite in these individuals.

Sensitivity of mouse lung fibroblasts heterozygous for GPx4 to oxidative stress.

Phospholipid hydroperoxide glutathione peroxidase (GPx4) is a member of the family of selenium-dependent enzymes that catalyze the reduction of cell membrane-bound phospholipid hydroperoxides in situ and thus protects against membrane damage. Overexpression of GPx4 protects cultured cells from phosphatidylcholine hydroperoxide (PCOOH)-induced loss of mitochondrial membrane potential and blocks cell death induced by treatment with various apoptotic agents. We have generated mice that are heterozygous for a GPx4 null allele (GPx4 +/-); the homozygous null genotype is embryonic lethal. We report that cultured lung fibroblasts (LFs) isolated from adult GPx4 +/- mice had approximately 50% of the GPx4 activity of LFs from GPx4 +/+ mice and were significantly more susceptible to H2O2, cadmium, and cumene hydroperoxide-induced cytotoxicity, as measured by neutral red assay. Both GPx4 +/+ and GPx4 +/- LFs were susceptible to PCOOH-induced cytotoxicity at a high PCOOH concentration. We also found that GPx4 +/- LFs have lower mitochondrial membrane potential, greater cardiolipin oxidation, and lower amounts of reduced thiols relative to GPx4 +/+ LFs, but are more resistant than GPx4 +/+ LFs to further decrements in these endpoints following PCOOH treatment. These results suggest that adult lung fibroblasts deficient in GPx4 may have upregulated compensatory mechanisms to deal with the highly oxidized environment in which they developed.

Identification of novel retinal target genes of thyroid hormone in the human WERI cells by expression microarray analysis.

Using the human WERI-Rb1 cell line as a model system, we performed a genome-wide search for retinal target genes of thyroid hormone (TH) via expression microarray analysis followed by quantitative real-time RT-PCR verification. We identified 12 novel retinal targets of TH, including 10 up-regulated genes (OPN1MW, OPN1LW, TIMP3, RP1L1, GNGT2, CRX, ARR3, GCAP1, IMPDH1, and PDE6C) and 2 down-regulated genes (GNGT1 and GNB3). In addition, we found a number of novel TH-targets that are not currently known to be retinal genes. This is the first report of human retinal targets regulated by thyroid hormone.

Mutually exclusive expression of the L and M pigment genes in the human retinoblastoma cell line WERI: Resetting by cell division.

The key steps in the evolution of full trichromatic color vision in primates include duplication of the ancestral pigment gene to form the L and M pigment gene array on the X chromosome, mutually exclusive expression of the L and M pigment genes in cone photoreceptors, and formation of a retinal mosaic with randomly distributed L and M cones. Previous work using transgenic mice has indicated that a locus control region adjacent to this array of genes plays an important role in their mutually exclusive expression in respective cone cells (Smallwood et al., 2002). However, the mechanism by which this is accomplished is unknown. We searched for a cellular model system to investigate the mechanism of this mutually exclusive expression. We previously showed that the undifferentiated human retinoblastoma cell line WERI expresses L and M cone opsin but not rod opsin genes. We now show that WERI cells express the L and M pigment genes in a mutually exclusive manner, in that either L or M pigment mRNA is expressed in a single cell. Importantly, clonal analysis showed that single WERI cells that express either L or M generate, upon cell division produce, a mixed population of L- or M-expressing cells. These results indicate, first, that cell division resets L or M pigment gene expression, most likely due to disassembly and reassembly of LCR-promoter DNA-protein complexes during cell division. Second, a retinal mosaic with near-random distribution of L and M cones may have been generated automatically after duplication of the ancestral gene to form the L and M pigment genes. Third, determination of L and M cone identity may not require external molecular cues during differentiation, and is consistent with the idea that L and M cones are not intrinsically different.

Genetics of variation in human color vision and the retinal cone mosaic.

Variation in human color vision is mainly caused by one common polymorphism (Ser180Ala) in the L pigment, and to the frequent presence of hybrid genes that encode pigments with various spectral properties. Both recombination and gene conversion between the highly homologous L and M pigment genes have generated wide variation in genotype and color vision phenotype. The S, M and L cones are distributed randomly in the central retina. Unlike S cones, M and L cones vary widely in number within the central retina. Determining the number of the three classes of cone and their special distribution in the living retina has significantly advanced the ability to correlate the cone mosaic in normal and color-defective subjects with the color vision phenotype. The transcription factors NR2E3, TRbeta2 and RXRgamma play crucial roles in establishment of the retinal cone mosaic during eye development.

Transcriptional regulation of the human hepatic lipase (LIPC) gene promoter.

Hepatic lipase (HL) plays a key role in the metabolism of plasma lipoproteins, and its level of activity requires tight regulation, given the association of both low and high levels with atherosclerosis and coronary artery disease. However, little is known about the factors responsible for HL expression. Here, we report that the human hepatic lipase gene (LIPC) promoter is regulated by hepatocyte nuclear factor 4alpha (HNF4alpha), peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), apolipoprotein A-I regulatory protein-1 (ARP-1), and hepatocyte nuclear factor 1alpha (HNF1alpha). Reporter analysis showed that HNF4alpha directly regulates the LIPC promoter via two newly identified direct repeat elements, DR1 and DR4. PGC-1alpha is capable of stimulating the HNF4alpha-dependent transactivation of the LIPC promoter. ARP-1 displaces HNF4alpha from the DR1 site and blocks its ability to activate the LIPC promoter. Induction by HNF1alpha requires the HNF1 binding site and upon cotransfection with HNF4alpha leads to an additive effect. In addition, the in vivo relevance of HNF4alpha in LIPC expression is shown by the ability of the HNF4alpha antagonist Medica 16 to repress endogenous LIPC mRNA expression. Furthermore, disruption of Hnf4alpha in mice prevents the expression of HL mRNA in liver. The overall effect these transcription factors have on HL expression will ultimately depend on the interplay between these various factors and their relative intracellular concentrations.

Common hepatic lipase gene promoter variant predicts the degree of neointima formation after carotid endarterectomy: impact of plaque composition and lipoprotein phenotype.

BACKGROUND: The common -514 C-T promoter polymorphism of the hepatic lipase gene (LIPC) and the cholesteryl ester transfer protein (CETP) gene TaqIB polymorphism affect atherogenesis. We investigated the potential relationship between these polymorphisms and the maximum-intima-media thickness (M-IMT) after carotid endarterectomy. METHODS: The LIPC and CETP genotypes were determined by PCR in 68 patients undergoing endarterectomy. Plaque specimens were analysed for cell composition by immunocytochemistry. Six month after surgery the M-IMT of the revascularized vessel was assessed by B-mode ultrasonography. RESULTS: The CC carriers had denser LDL particles (p<0.0005), an abundance of macrophages (p<0.0005), fewer SMCs in the carotid plaque (p<0.0005), and higher prevalence of cerebrovascular events (72% versus 28%, p=0.002) compared to CT/TT carriers. After endarterectomy, CC carriers showed a lower M-IMT than the CT/TT group (1.36 mm versus 1.76 mm, p=0.04). No association between the CETP polymorphism and either carotid plaque cellular composition or M-IMT was observed. In a multivariate analysis, M-IMT was associated with plaque cell composition (macrophages, r=-0.39; SMC, r=0.44; p<0.005 for both) but not with pre-operative LDL-C, HDL-C, triglycerides, or LDL density. CONCLUSIONS: The LIPC promoter -514 C-T polymorphism is associated with a significantly reduced development of neointima after surgery. This effect seems to be mediated by scarcity of SMC in the plaque of CC carriers who display an excess prevalence of cerebrovascular events prior endarterectomy but are at low risk for restenosis. The pre-operative lipid phenotype plays a marginal role in the neointima formation.

Expression of rinx/vsx1 during postnatal eye development in cone-bipolar, differentiating ganglion, and lens fiber cells.

PURPOSE: To investigate the expression pattern of the homeobox transcription factor Rinx (also referred to as Vsx1) during postnatal eye development of the mouse. METHODS: We cloned the mouse Rinx gene, inferred the sequence of the encoded protein, and prepared polyclonal antibodies against it. Immunohistochemical analysis (IHC) and in situ hybridization were employed to localize Rinx in postnatal and adult mouse eyes. Double-labeled IHC either with anti-protein kinase C (PKC, a marker of rod bipolar cells) or anti-vimentin (a marker of Muller glial cells) antibodies was performed in the adult retina. Rinx mRNA was also analyzed by reverse transcription-polymerase chain reaction in the lens. RESULTS: At P0 and P4 (postnatal days), Rinx-immunoreactive cells included retinal ganglion cells (RGC), cells of the innermost nuclear layer (INL) and of presumptive INL, differentiating lens fiber cells, and a few cells of the presumptive outer nuclear layer (ONL). At P8, both Rinx protein and mRNA were detected in the middle of the INL, and in RGC, but not in the lens. When the mice were 8 weeks of age, only a subset of nuclei in the outer half of the INL expressed both Rinx protein and mRNA. Double-labeling IHC indicated that Rinx- and either PKC- or vimentin-labeled cells were not colocalized. Therefore, Rinx is most likely expressed in adult cone bipolar cells and possibly in horizontal cells. CONCLUSIONS: Rinx may play important roles in the differentiation and maintenance of cone bipolar cells. Rinx is unique among members of this family of homeodomain proteins in that it may also be involved in differentiation of RGC and lens fiber cells.

Apolipoprotein L-I is positively associated with hyperglycemia and plasma triglycerides in CAD patients with low HDL.

Apolipoprotein L-I (apoL-I) is present on a subset of HDL particles and is positively correlated with plasma triglycerides (TGs). We measured plasma apoL-I levels in coronary artery disease (CAD) subjects with low HDL who were enrolled in an angiographic CAD prevention trial. At baseline, apoL-I levels (n = 136; range, 2.2-64.1 mug/ml) were right skewed with a large degree of variability. Multivariate analysis for biological determinants of apoL-I revealed that the log of VLDL-TG (+0.17; P < 0.05) and hyperglycemia (HG; +0.26; P < 0.005) independently predicted apoL-I level. Hyperglycemic patients (n = 24) had mean apoL-I levels >50% higher than normoglycemic subjects (n = 112; 13.2 vs. 8.3 mug/ml, respectively; P < 0.001). No relationship between apoL-I level and change in CAD was found (r = 0.06, P = 0.49). Simvastatin-niacin therapy did not alter apoL-I levels (n = 34; P = 0.27), whereas antioxidant vitamins alone increased apoL-I by >50% (n = 36; P < 0.01). Genotyping of a known apoL-I polymorphism (Lys166Glu) did not independently account for any of the variability in apoL-I levels. In conclusion, we found TG and HG to be the strongest predictors of apoL-I within a dyslipidemic CAD population. These data provide further characterization of the novel HDL-associated apoL-I.

Molecular genetics of color-vision deficiencies.

The normal X-chromosome-linked color-vision gene array is composed of a single long-wave-sensitive (L-) pigment gene followed by one or more middle-wave-sensitive (M-) pigment genes. The expression of these genes to form L- or M-cones is controlled by the proximal promoter and by the locus control region. The high degree of homology between the L- and M-pigment genes predisposed them to unequal recombination, leading to gene deletion or the formation of L/M hybrid genes that explain the majority of the common red-green color-vision deficiencies. Hybrid genes encode a variety of L-like or M-like pigments. Analysis of the gene order in arrays of normal and deutan subjects indicates that only the two most proximal genes of the array contribute to the color-vision phenotype. This is supported by the observation that only the first two genes of the array are expressed in the human retina. The severity of the color-vision defect is roughly related to the difference in absorption maxima (lambda(max)) between the photopigments encoded by the first two genes of the array. A single amino acid polymorphism (Ser180Ala) in the L pigment accounts for the subtle difference in normal color vision and influences the severity of red-green color-vision deficiency. Blue-cone monochromacy is a rare disorder that involves absence of L- and M-cone function. It is caused either by deletion of a critical region that regulates expression of the L/M gene array, or by mutations that inactivate the L- and M-pigment genes. Total color blindness is another rare disease that involves complete absence of all cone function. A number of mutants in the genes encoding the cone-specific alpha- and beta-subunits of the cGMP-gated cation channel as well as in the alpha-subunit of transducin have been implicated in this disorder.

Cone visual pigments of the Australian marsupials, the stripe-faced and fat-tailed dunnarts: sequence and inferred spectral properties.

Studies of color vision in marsupial mammals have been very limited. Two photoreceptor genes have been characterized from the tammar wallaby, but a third cone pigment was suggested by microspectrophotometric measurements on cone photoreceptors in two other species, including the fat-tailed dunnart, Sminthopsis crassicaudata. To determine the sequence and infer absorption maxima of the cone photoreceptor pigments of S. crassicaudata and the related stripe-faced dunnart (Sminthopsis macroura), we have used evolutionarily conserved sequences of the cone pigments of other species, including the tammar wallaby, to design primers to amplify the S. macroura and S. crassicaudata pigment sequences by the polymerase chain reaction (PCR) using genomic DNA or retinal cDNA as a template. These primers will be useful for amplifying cone opsin coding sequences from a variety of vertebrates. Amplified products were directly sequenced to determine gene structure and coding sequences. The inferred amino acid sequences of the cone visual pigments indicated that both species have middle-wave-sensitive (MWS) pigments with a predicted absorption maximum (lambda(max)) at 530 nm, and ultraviolet-sensitive (UVS) pigments with a predicted lambda(max) at 360 nm. The MWS pigments of the two species differ by two, and UVS by three amino acid positions. No evidence was obtained for a third cone pigment in either species.

Molecular genetics of colour vision deficiencies.

Common variation in colour vision exists among both colour normal and colour deficient subjects. Differences at a few amino acid positions that influence the spectra of the L and M cone pigments account for most of this variation. The genes encoding the L and M photopigments are arranged in head-to-tail arrays on the X-chromosome, beginning with the L and followed by one or more M pigment genes. The L and M pigment genes are highly homologous, which predisposed them to unequal crossing over (recombination) resulting in gene deletions and in formation of L/M hybrid genes that encode a variety of pigments with either L-like or M-like spectra that account for the majority of colour vision defects. Only the first two pigment genes of the L/M array are expressed in the retina and, therefore, need to be considered in predicting colour vision. A common single amino acid polymorphism (serine or alanine) at position 180 of the L-pigment plays an important role both in variation in normal colour vision and in the severity of colour vision defects. Blue cone monochromacy is a rare form of colour vision deficiency that results from mutations that abolish function of both the L and M pigment genes. All the above defects are inherited as X-linked recessive traits. Tritanopia is also a rare autosomal dominant colour vision defect caused by mutations in the S pigment gene located on chromosome 7. Total colour blindness (achromatopsia or rod monochromacy) is a rare autosomal recessive trait caused by mutations in genes encoding the proteins of the photoreceptor cation channel or cone transducin that are essential for function of all classes of cone.

X-linked high myopia associated with cone dysfunction.

OBJECTIVE: Bornholm eye disease (BED) consists of X-linked high myopia, high cylinder, optic nerve hypoplasia, reduced electroretinographic flicker with abnormal photopic responses, and deuteranopia. The disease maps to chromosome Xq28 and is the first designated high-grade myopia locus (MYP1). We studied a second family from Minnesota with a similar X-linked phenotype, also of Danish descent. All affected males had protanopia instead of deuteranopia. METHODS: X chromosome genotyping, fine-point mapping, and haplotype analysis of the DNA from 22 Minnesota family individuals (8 affected males and 5 carrier females) and 6 members of the original family with BED were performed. Haplotype comparisons and mutation screening of the red-green cone pigment gene array were performed on DNA from both kindreds. RESULTS: Significant maximum logarithm of odds scores of 3.38 and 3.11 at theta = 0.0 were obtained with polymorphic microsatellite markers DXS8106 and DXYS154, respectively, in the Minnesota family. Haplotype analysis defined an interval of 34.4 cM at chromosome Xq27.3-Xq28. Affected males had a red-green pigment hybrid gene consistent with protanopia. We genotyped Xq27-28 polymorphic markers of the family with BED, and narrowed the critical interval to 6.8 cM. The haplotypes of the affected individuals were different from those of the Minnesota pedigree. Bornholm eye disease-affected individuals showed the presence of a green-red hybrid gene consistent with deuteranopia. CONCLUSIONS: Because of the close geographic origin of the 2 families, we expected affected individuals to have the same haplotype in the vicinity of the same mutation. Mapping studies, however, suggested independent mutations of the same gene. The red-green and green-red hybrid genes are common X-linked color vision defects, and thus are unrelated to the high myopia and other eye abnormalities in these 2 families. CLINICAL RELEVANCE: X-linked high myopia with possible cone dysfunction has been mapped to chromosome Xq28 with intervals of 34.4 and 6.8 centimorgan for 2 families of Danish origin.