Biomedical subjects

Julia E Richards

Publications and source records attributed to Julia E Richards.

17 recordsLinked to original sources

PubMed2007

Evaluation of the beta2-adrenergic receptor gene as a candidate glaucoma gene in 2 ancestral populations.

OBJECTIVE: To determine whether the beta(2)-adrenergic receptor (ADRB2) gene is a glaucoma susceptibility locus. DESIGN AND METHODS: The design was an association study stratified by ancestry (white vs black African) and disease (primary open-angle glaucoma vs control subjects). The ADRB2 single nucleotide polymorphisms were determined by sequencing, and the haplotypes of the common single nucleotide polymorphisms affecting codons 16 and 27 were phased by allele-specific polymerase chain reaction and restriction enzyme digestion. We analyzed the association of single nucleotide polymorphisms and haplotypes by ancestry and disease with the Fisher exact test, chi(2) test, and standardized Pearson residual. RESULTS: A total of 583 subjects underwent genotyping (156 white subjects with primary open-angle glaucoma; 143 subjects of black African ancestry with primary open-angle glaucoma; 148 white controls; and 136 controls of black African ancestry). There were no differences in ADRB2 alleles and haplotypes between the primary open-angle glaucoma and control groups, whether analyzed together or by ancestry. Previously described ancestry-based differences in allele frequencies were found. We also found ancestry-based differences in ADRB2 haplotypes. CONCLUSION: The ADRB2 gene was not a glaucoma susceptibility locus in our study population. CLINICAL RELEVANCE: Because this gene is not a disease locus, we can now study the role of ADRB2 haplotypes in the glaucoma risk factor of intraocular pressure fluctuation and variation in intraocular pressure response to beta-blockers.

Aged↗

PubMed2007

Differential expression profile prioritization of positional candidate glaucoma genes: the GLC1C locus.

OBJECTIVES: To develop and apply a model for prioritization of candidate glaucoma genes. METHODS: This Affymetrix GeneChip (Affymetrix, Santa Clara, Calif) study of gene expression in primary culture human trabecular meshwork cells uses a positional differential expression profile model for prioritization of candidate genes within the GLC1C genetic inclusion interval. RESULTS: Sixteen genes were expressed under all conditions within the GLC1C interval. TMEM22 was the only gene within the interval with differential expression in the same direction under both conditions tested. Two genes, ATP1B3 and COPB2, are of interest in the context of a protein-misfolding model for candidate selection. SLC25A36, PCCB, and FNDC6 are of lesser interest because of moderate expression and changes in expression. Transcription factor ZBTB38 emerges as an interesting candidate gene because of the overall expression level, differential expression, and function. CONCLUSIONS: Only 1 gene in the GLC1C interval fits our model for differential expression under multiple glaucoma risk conditions. The use of multiple prioritization models resulted in filtering 7 candidate genes of higher interest out of the 41 known genes in the region. CLINICAL RELEVANCE: This study identified a small subset of genes that are most likely to harbor mutations that cause glaucoma linked to GLC1C.

Adolescent↗

PubMed2007

Myocilin Gly252Arg mutation and glaucoma of intermediate severity in Caucasian individuals.

OBJECTIVE: To determine the phenotype of an Australian pedigree with the myocilin (MYOC) Gly252Arg mutation, comparing it with other pedigrees carrying the same mutation. METHODS: All recruited subjects underwent a comprehensive clinical examination, including optic disc assessment, applanation tonometry, and visual field measurement. Mutation analysis was performed through direct sequencing. Haplotype analysis was performed using microsatellite markers around the MYOC gene. RESULTS: Eight Gly252Arg mutation carriers with glaucoma were identified from the same pedigree. Carriers' mean +/- SD age at diagnosis was 46.3 +/- 11.4 years (range, 31-60 years). Highest recorded intraocular pressure ranged from 27 to 42 mm Hg (mean +/- SD, 32.4 +/- 5.6 mm Hg). Cup-disc ratios in the worst eye ranged from 0.6 to 0.9. Six of the 8 individuals had undergone filtration surgery. A common founding haplotype between MY5 and D1S218 was found for Caucasian individuals tested with this mutation. One subject was compound heterozygotic for the MYOC Gly252Arg mutation and a novel MYOC Gly244Val variant. CONCLUSIONS: Although a common founder for Gly252Arg across Caucasian subjects was found, the phenotype from this Australian MYOC mutation-carrying pedigree is less severe than previously described. The severity of glaucoma caused by the Gly252Arg mutation may be similar to the Thr377Met MYOC mutation, yet is more severe than the most common Gln368Stop mutation. CLINICAL RELEVANCE: Since its implication in glaucoma, much work has been performed investigating the clinical features of MYOC-related glaucoma. Given the strong genotype-phenotype correlations with MYOC disease-causing variants, health care professionals armed with such molecular information are able to accurately counsel patients on their likely disease course. Our work suggests that the disease associated with MYOC Gly252Arg is less severe than previously described in other pedigrees with this specific mutation.

Adult↗

PubMed2006

Gene expression profile of human trabecular meshwork cells in response to long-term dexamethasone exposure.

PURPOSE: Topical use of dexamethasone has long been associated with steroid induced-glaucoma, although the mechanism is unknown. We applied a strict filtering of comparative microarray data to more than 18,000 genes to evaluate global gene expression of cultured human trabecular meshwork cells in response to treatment with dexamethasone. METHODS: Three human trabecular meshwork cell primary cultures from nonglaucomatous donors were incubated with and without dexamethasone for 21 days. Relative gene expression was evaluated by analysis of U133A GeneChip and the results validated using quantitative polymerase chain reaction (PCR). RESULTS: Application of strict filtering to include only genes with statistically significant differences in gene expression across all three trabecular meshwork cell cultures produced a list of 1,260 genes. Significant changes in signal level were observed, including 23 upregulated and 18 downregulated genes that changed greater than three fold in each of three cell cultures. Using quantitative PCR we found changes greater than a thousand fold for two genes (SLP1 and SAA2) and changes greater than a hundred fold for another five genes (ANGPTL7, MYOC, SAA1, SERPINA3, and ZBTB16). CONCLUSIONS: Expression changes in trabecular meshwork cells in response to dexamethasone treatment indicate that a group of actins and actin-associated proteins are involved in the development of cross-linked actin networks that form in response to dexamethasone. A trend was identified toward decreased expression of protease genes accompanied by an increased expression of protease inhibitors. Such a trend in nonproteasomal proteolysis conceivably affects gene product levels above the level of transcription. Only two genes, MYOC and IGFBP2, showed significantly elevated expression after dexamethasone treatment in our study and the other three previously published reports of primary culture trabecular meshwork cell gene expression.

Adolescent↗

PubMed2006

Concordance of aqueous humor flow in the morning and at night in normal humans.

PURPOSE: To test the hypothesis that an individual shows concordance of aqueous humor flow in the morning and at night in a prospective inpatient fluorophotometry study in healthy subjects. METHODS: Flow was measured in each eye every hour between 8 AM and noon and every 2 hours between midnight and 6 AM. Morning and nighttime flows were analyzed for differences between eyes and for differences between these two time points. Concordance of individual morning and nighttime flows were studied by categorization into low, medium, or high tertiles, dot plot, and ordinary least-squares regression (OLS) scatter plot. RESULTS: In 28 subjects, the flow was similar between eyes within a subject with healthy eyes. In the one eye examined in each subject, the average flow was 3.12 +/- 1.09 muL/min in the morning, which decreased significantly to 1.59 +/- 0.58 muL/min at night. During each time period, the individual flow data were normally distributed. Concordance of an individual's morning and nighttime flows was 68%. A scatter plot of morning versus nighttime flows also supported concordance with an OLS regression fit of r(2) = 0.45. CONCLUSIONS: The results provide evidence that aqueous humor flow is similar between eyes, that flow variation shows a normal distribution, and that individuals show a concordance of flow in the morning and at night. These observations support the posit that aqueous humor flow, which is a factor that contributes to the important clinical risk factor of IOP variation, is amenable to study as a quantitative trait.

Adolescent↗

PubMed2005

Ordered subset analysis supports a glaucoma locus at GLC1I on chromosome 15 in families with earlier adult age at diagnosis.

Open angle glaucoma (OAG) is a complex disorder with varying etiologies due to multiple genes and environmental effects. This genetic heterogeneity can confound efforts to map loci. Increased homogeneity in a sample can be achieved using either ordered subset analysis (OSA) which groups families, or individual OSA (IOSA), which groups individuals based on disease related covariates. Recently, GLC1I was mapped to 15q11-13 in families with early adult onset of OAG. We tested for linkage to GLC1I in an independent sample of 167 individuals in 25 multiplex OAG families of European descent. We carried out nonparametric linkage analysis on the complete set of 25 families and obtained a maximum LOD score of 1.00 at 9.0 cM. Using mean age at diagnosis (AAD) across the affected individuals within each family to order the families as a proxy for age at onset, we found a maximum OSA LOD score of 2.09 (p=0.021) at 26.1 cM. The mean (+/-s.d.) AAD across the 14 earlier AAD families that contributed to the OSA LOD score was 50.6 years (+/-5.38); the mean AAD for the other 1210 later AAD families that did not contribute to the OSA LOD score (the high-AAD) was 61.7 years (+/-3.50). We also ran IOSA on our families using AAD as our covariate on which to subset affected individuals. The maximum LOD score was 1.01 at 14.3 cM when ordering subjects from early to late AAD. Ordered subset analysis of this sample has provided evidence of linkage close to the previously identified GLC1I glaucoma locus on 15q11-13 in families with middle-aged mean age at diagnosis.

Adolescent↗

PubMed2005

Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells.

Posterior polymorphous corneal dystrophy (PPCD, also known as PPMD) is a rare disease involving metaplasia and overgrowth of corneal endothelial cells. In patients with PPCD, these cells manifest in an epithelial morphology and gene expression pattern, produce an aberrant basement membrane, and, sometimes, spread over the iris and nearby structures in a way that increases the risk for glaucoma. We previously mapped PPCD to a region (PPCD3) on chromosome 10 containing the gene that encodes the two-handed zinc-finger homeodomain transcription factor TCF8. Here, we report a heterozygous frameshift mutation in TCF8 that segregates with PPCD in the family used to map PPCD3 and four different heterozygous nonsense and frameshift mutations in TCF8 in four other PPCD probands. Family reports of inguinal hernia, hydrocele, and possible bone anomalies in affected individuals suggest that individuals with TCF8 mutations should be examined for nonocular anomalies. We detect transcripts of all three identified PPCD genes (VSX1, COL8A2, and TCF8) in the cornea. We show presence of a complex (core plus secondary) binding site for TCF8 in the promoter of Alport syndrome gene COL4A3, which encodes collagen type IV alpha 3, and we present immunohistochemical evidence of ectopic expression of COL4A3 in corneal endothelium of the proband of the original PPCD3 family. Identification of TCF8 as the PPCD3 gene provides a valuable tool for the study of critical gene regulation events in PPCD pathology and suggests a possible role for TCF8 mutations in altered structure and function of cells lining body cavities other than the anterior chamber of the eye. Thus, this study has identified TCF8 as the gene responsible for approximately half of the cases of PPCD, has implicated TCF8 mutations in developmental abnormalities outside the eye, and has presented the TCF8 regulatory target, COL4A3, as a key, shared molecular component of two different diseases, PPCD and Alport syndrome.

Autoantigens↗

PubMed2005

Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration.

Age-related macular degeneration (AMD) is a genetically heterogeneous disease that leads to progressive and irreversible vision loss among the elderly. Inflammation, oxidative damage, cholesterol metabolism and/or impaired function of retinal pigment epithelium (RPE) have been implicated in AMD pathogenesis. We examined toll-like receptor 4 (TLR4) as a candidate gene for AMD susceptibility because: (i) the TLR4 gene is located on chromosome 9q32-33, a region exhibiting evidence of linkage to AMD in three independent reports; (ii) the TLR4-D299G variant is associated with reduced risk of atherosclerosis, a chronic inflammatory disease with subendothelial accumulation; (iii) the TLR4 is not only a key mediator of proinflammatory signaling pathways but also linked to regulation of cholesterol efflux and (iv) the TLR4 participates in phagocytosis of photoreceptor outer segments by the RPE. We examined D299G and T399I variants of TLR4 in a sample of 667 unrelated AMD patients and 439 unrelated controls, all of Caucasian ancestry. Multiple logistic regression demonstrated an increased risk of AMD in carriers of the G allele at TLR4 residue 299 (odds ratio=2.65, P=0.025), but lack of an independent effect by T399I variant. TLR4-D299G showed an additive effect on AMD risk (odds ratio=4.13, P=0.002) with allelic variants of apolipoprotein E (APOE) and ATP-binding cassette transporter-1 (ABCA1), two genes involved in cholesterol efflux. Interestingly, the effect of TLR4, APOE and ABCA1 variants on AMD susceptibility was opposite to that of association with atherosclerosis risk. Our data provide evidence of a link between multiple diverse mechanisms underlying AMD pathogenesis.

Aged↗

PubMed2005

Effect of intravitreal triamcinolone acetonide on susceptibility to experimental bacterial endophthalmitis and subsequent response to treatment.

OBJECTIVES: Recent reports of high endophthalmitis rates after intravitreal triamcinolone acetonide injection have raised concerns about the safety of this treatment. We sought to evaluate the effect of intravitreal triamcinolone injection on (1) the susceptibility to experimental bacterial endophthalmitis and (2) the subsequent therapeutic response to antibiotic treatment. DESIGN: For the susceptibility study, the right eye of 40 New Zealand white rabbits received an intravitreal injection of a known quantity of Staphylococcus epidermidis organisms. Half of the eyes received a simultaneous intravitreal injection of triamcinolone acetonide, 4 mg. All eyes were examined daily for signs of endophthalmitis (photophobia, conjunctival injection, and vitritis) using standardized grading protocols (scaled from 0 to 4 with increasing severity). On day 7, vitreous cultures were obtained. For the therapeutic response study, the right eye of 12 rabbits received an intravitreal injection of S epidermidis organisms sensitive to vancomycin. Half of the eyes received a simultaneous intravitreal injection of triamcinolone acetonide, 4 mg. All 12 eyes received an intravitreal injection of vancomycin hydrochloride, 1 mg, on development of the first signs of endophthalmitis. All eyes were examined daily for 7 additional days. On day 7 after treatment, vitreous cultures were obtained. RESULTS: In the susceptibility study, all 40 eyes developed signs of endophthalmitis. In eyes that received intravitreal bacteria plus triamcinolone, 17 (85%) of the 20 vitreous cultures were positive, whereas only 6 (30%) were positive in the 20 eyes receiving bacteria alone (P = .001). The vitritis was significantly increased in the bacteria plus triamcinolone group compared with the bacteria-only group (17 of 20 vs 7 of 20 with 4+ vitritis, respectively; P = .003). In the therapeutic response study, all 12 eyes developed clinical signs of endophthalmitis within 48 hours. All vitreous samples obtained 7 days after intravitreal vancomycin injection were culture negative. However, the severity of vitritis at the time of vitreous sampling was less in the eyes receiving triamcinolone plus bacteria compared with eyes receiving bacteria alone (0 of 6 vs 5 of 6 with 4+ vitritis, respectively; P = .02). CONCLUSIONS: In eyes with experimentally induced bacterial endophthalmitis, the presence of intravitreal triamcinolone results in a higher culture-positive rate and a higher degree of inflammation, suggesting an impaired ocular immune response and greater susceptibility to infection. However, in eyes with experimentally induced bacterial endophthalmitis receiving early treatment with intravitreal antibiotics, triamcinolone appears to suppress the ocular inflammatory response without impairing the therapeutic effect. CLINICAL RELEVANCE: These data suggest that caution must be exercised when combining intravitreal triamcinolone injection with intraocular surgery.

Animals↗

PubMed2004

A locus for posterior polymorphous corneal dystrophy (PPCD3) maps to chromosome 10.

Posterior polymorphous corneal dystrophy (PPCD) is an autosomal dominant disorder characterized by corneal endothelial abnormalities, which can lead to blindness due to loss of corneal transparency and sometimes glaucoma. We mapped a new locus responsible for PPCD in a family in which we excluded the previously reported PPCD locus on 20q11, and the region containing COL8A2 on chromosome 1. Results of a 317-marker genome scan provided significant evidence of linkage of PPCD to markers on chromosome 10, with single-point LOD scores of 2.63, 1.63, and 3.19 for markers D10S208 (at (circumflex)theta = 0.03), D10S1780 (at (circumflex)theta = 0.00), and D10S578 (at (circumflex)theta = 0.06). A maximum multi-point LOD score of 4.35 was found at marker D10S1780. Affected family members shared a haplotype in an 8.55 cM critical interval that was bounded by markers D10S213 and D10S578. Our finding of another PPCD locus, PPCD3, on chromosome 10 indicates that PPCD is genetically heterogeneous. Guttae, a common corneal finding sometimes observed along with PPCD, were found among both affected and unaffected members of the proband's sib ship, but were absent in the younger generations of the family. Evaluation of phenotypic differences between family members sharing the same affected haplotype raises questions about whether differences in disease severity, including differences in response to surgical interventions, could be due to genetic background or other factors independent of the PPCD3 locus.

Adult↗

PubMed2004

Age-related macular degeneration: a high-resolution genome scan for susceptibility loci in a population enriched for late-stage disease.

Age-related macular degeneration (AMD) is a complex multifactorial disease that affects the central region of the retina. AMD is clinically heterogeneous, leading to geographic atrophy (GA) and/or choroidal neovascularization (CNV) at advanced stages. Considerable data exists in support of a genetic predisposition for AMD. Recent linkage studies have provided evidence in favor of several AMD susceptibility loci. We have performed a high-resolution (5-cM) genome scan of 412 affected relative pairs that were enriched for late-stage disease (GA and/or CNV). Nonparametric linkage analysis was performed using two different diagnostic criteria and also by dividing the affected individuals according to GA or CNV phenotype. Our results demonstrate evidence of linkage in regions that were suggested in at least one previous study at chromosomes 1q (236-240 cM in the Marshfield genetic map), 5p (40-50 cM), and 9q (111 cM). Multipoint analysis of affected relatives with CNV provided evidence of additional susceptibility loci on chromosomes 2p (10 cM) and 22q (25 cM). A recently identified Gln5345Arg change in HEMICENTIN-1 on chromosome 1q25 was not detected in 274 affected members in the restricted group with AMD, 346 additional patients with AMD, and 237 unaffected controls. Our results consolidate the chromosomal locations of several AMD susceptibility loci and, together with previous reports, should facilitate the search for disease-associated sequence variants.

Aging↗

PubMed2004

Stem cell therapy for ocular disorders.

Cell injury or degeneration occurs in a number of blinding diseases. Therapy has classically consisted of preventing the initial injury or increasing the resistance of cells to injury (cytoprotection). Recently, it has become possible to repopulate tissue compartments with stem cells. This article presents a current summary of ocular stem cell research and applications to disease. It is based on presentations and discussions from the July 2002 international conference "Stem Cells and Glaucoma" sponsored by the Glaucoma Foundation. This meeting, the first of its kind, brought together ophthalmologists, geneticists, immunologists, and developmental biologists working on stem cell development and applications in both human and animal models.

Animals↗

PubMed2004

A novel mutation in the PITX2 gene in a family with Axenfeld-Rieger syndrome.

PURPOSE: To determine the underlying genetic cause of Axenfeld-Rieger syndrome (ARS) in a three-generation family. INTRODUCTION: ARS is a multisystem, autosomal dominant disorder characterized by specific ocular and non-ocular anomalies sometimes caused by mutations in the transcription factor gene, PITX2. METHODS: The three coding exons of the PITX2 gene, i.e., exons 2, 3, and 4, in affected and unaffected subjects were amplified by polymerase chain reaction (PCR) and sequenced. The PCR products of exon 4 were subcloned and sequenced to confirm the nature of the mutation. RESULTS: A deletion of thymine (T) 1261 was identified, creating a frameshift mutation in codon 227. This change is predicted to create 11 novel amino acids downstream, followed by premature truncation of the protein. CONCLUSIONS: This mutation highlights the functional importance of a conserved 14-amino acid sequence at the C-terminus of the protein thought to be important in repressing DNA binding and in protein-protein interactions.

Abnormalities, Multiple↗

PubMed2003

Clinicopathologic correlation and genetic analysis in a case of posterior polymorphous corneal dystrophy.

PURPOSE: To evaluate the clinical history, histopathology, and genetics of posterior polymorphous corneal dystrophy (PPMD) in a woman with a prominent retrocorneal membrane. DESIGN: Observational case report and genetic analysis of her family, UM:139. METHODS: Records were reviewed from a case and associated family members. The diagnosis of PPMD was based on clinical examination, immunohistochemical staining, electron microscopy, and screening of genetic markers from regions previously reported to be associated with PPMD. RESULTS: Over 17 years, the proband with PPMD had 25 ocular procedures performed for glaucoma, cataract, cornea, retina, and postoperative problems. A prominent retrocorneal membrane grew onto the crystalline lens and intraocular lens (IOL). Histopathology revealed stratified epithelial-like cells on iris from an iridectomy and stratified corneal endothelium on a corneal button. Electron microscopy on the cornea revealed microvilli, tonofilaments, and desmosomes consistent with endothelial transformation, which was confirmed by positive anticytokeratin (CK) AE1/AE3 and CAM 5.2 immunoreactivity. Negative immunoreactivity in epithelium and positive in endothelium with anti-CK 7 supported the diagnosis of PPMD rather than epithelial downgrowth. Multiple relatives were affected with PPMD with apparent autosomal dominant inheritance, but surprisingly, the PPMD, congenital hereditary endothelial dystrophy 1 (CHED1) and CHED2 loci on chromosome 20 and the collagen, type VIII, alpha-2 (COL8A2) gene were excluded by linkage and haplotype analyses. CONCLUSIONS: We are unaware of previous PPMD reports describing the unusual feature of a retrocorneal membrane extending onto the crystalline lens and IOL. In addition, this family suggests another PPMD locus.

Biomarkers↗

PubMed2003

Septuagenarian's phenotype leads to ascertainment of familial MYOC gene mutation.

PURPOSE: To report a family with a myocilin (MYOC) gene mutation ascertained on the basis of the phenotype of the 71-year-old proband with juvenile-onset primary open-angle glaucoma (JOAG). PATIENTS AND METHODS: A thorough patient history of the proband and review of medical records revealed that a filtering procedure performed 50 years before had controlled the intraocular pressure (IOP) and prevented optic disc damage and visual field loss until the bleb failed after cataract surgery. Patient characteristics and history led to suspicion of a mutation in the MYOC gene. Mutation screening and clinical evaluation of the proband and family members were undertaken. RESULTS: A Val426Phe mutation was found in the JOAG proband and in 3 other blood relatives with glaucoma. The mutation was not present in unaffected relatives. CONCLUSIONS: A functioning filtering procedure performed 50 years before the current study was all that was needed to prevent glaucomatous damage and control IOP in the proband. Once the bleb failed, increased IOP led to damage in a relatively brief period of time. Although not every JOAG patient has the MYOC mutation, there is a somewhat typical MYOC phenotype that may predict an increased chance of harboring a MYOC mutation. Use of such phenotype information in evaluating whether to screen older patients can lead to identification of families at risk for open-angle glaucoma.

Adolescent↗

PubMed2002

X-linked recessive atrophic macular degeneration from RPGR mutation.

We mapped a new X-linked recessive atrophic macular degeneration locus to Xp21.1-p11.4 and show allelic involvement of the gene RPGR, which normally causes severe peripheral retinal degeneration leading to global blindness. Ten affected males whom we examined had primarily macular atrophy causing progressive loss of visual acuity with minimal peripheral visual impairment. One additional male showed extensive macular degeneration plus peripheral loss of retinal pigment epithelium and choriocapillaries. Full-field electroretinograms (ERGs) showed normal cone and rod responses in some affected males despite advanced macular degeneration, emphasizing the dissociation of atrophic macular degeneration from generalized cone degenerations, including X-linked cone dystrophy (COD1). The RPGR gene nonsense mutation G-->T at open reading frame (ORF)15+1164 cosegregated with the disease and may create a donor splice site. Identification of an RPGR mutation in atrophic maculardegeneration expands the phenotypic range associated with this gene and provides a new tool for the dissection of the relationship between clinically different retinal pathologies.

Adult↗

PubMed2001

Retinal dystrophy due to paternal isodisomy for chromosome 1 or chromosome 2, with homoallelism for mutations in RPE65 or MERTK, respectively.

Uniparental disomy (UPD) is a rare condition in which a diploid offspring carries a chromosomal pair from a single parent. We now report the first two cases of UPD resulting in retinal degeneration. We identified an apparently homozygous loss-of-function mutation of RPE65 (1p31) in one retinal dystrophy patient and an apparently homozygous loss-of-function mutation of MERTK (2q14.1) in a second retinal dystrophy patient. In both families, the gene defect was present in the patient's heterozygous father but not in the patient's mother. Analysis of haplotypes in each nuclear kindred, by use of DNA polymorphisms distributed along both chromosomal arms, indicated the absence of the maternal allele for all informative markers tested on chromosome 1 in the first patient and on chromosome 2 in the second patient. Our results suggest that retinal degeneration in these individuals is due to apparently complete paternal isodisomy involving reduction to homoallelism for RPE65 or MERTK loss-of-function alleles. Our findings provide evidence for the first time, in the case of chromosome 2, and confirm previous observations, in the case of chromosome 1, that there are no paternally imprinted genes on chromosomes 1 and 2 that have a major effect on phenotype.

Adolescent↗