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Biomedical subjects

David A Mackey

Publications and source records attributed to David A Mackey.

At least 37 records · Page 2Linked to original sources
PubMed2005

Evidence for a novel glaucoma locus at chromosome 3p21-22.

Primary open-angle glaucoma (POAG) is one of the leading causes of blindness in the world. It is a clinically variable group of diseases with the majority of cases presenting as the late onset adult type. Several chromosomal loci have been implicated in disease aetiology, but causal mutations have only been identified in a small proportion of glaucoma. We have previously described a large six-generation Tasmanian family with POAG exhibiting genetic heterogeneity. In this family, approximately one third of affected individuals presented with a glutamine-368-STOP (Q368STOP) mutation in the myocilin gene. We now use a Markov Chain Monte Carlo (MCMC) method to identify a second disease region in this family on the short arm of chromosome 3. This disease locus was initially mapped to the marker D3S1298 and a subsequent minimum disease region of 9 cM between markers D3S1298 and D3S1289 was identified through additional mapping. The region did not overlap with any previously described locus for POAG. Using a multiplicative relative risk model, we identified a positive association between this region and the Q368STOP mutation of myocilin on chromosome 1 in affected individuals. These findings provide evidence of a new autosomal dominant glaucoma locus on the short arm of chromosome 3.

Chromosome Mapping↗
PubMed2005

The Q368STOP myocilin mutation in a population-based cohort: the Blue Mountains Eye Study.

PURPOSE: To investigate the prevalence of the Q368STOP myocilin mutation in a population-based cohort: the Blue Mountains Eye Study (BMES). DESIGN: Population-based study. METHODS: DNA was extracted from 2,142 individuals collected through the BMES, including 31 individuals with glaucoma. All individuals were screened for the presence of the Q368STOP mutation of myocilin. Genotyping of the microsatellite markers My5, My3, D1S2815, and D1S1619 was also undertaken. RESULTS: None of the 31 open-angle glaucoma-positive individuals presented with the Q368STOP mutation. However, two individuals (aged 56 and 72) with no clinical signs of OAG, were identified with this mutation. Allele sharing at the four microsatellite markers defining the Q368STOP disease haplotype for OAG was found in these two individuals. CONCLUSIONS: The Q368STOP myocilin mutation occurs at a low prevalence (0.09%) in a general, older population.

Aged↗
PubMed2005

A common disease haplotype for the Q368STOP mutation of the myocilin gene in Australian and Canadian glaucoma families.

PURPOSE: To ascertain whether there is a common disease haplotype for the Q368STOP mutation of the myocilin gene in Australian and Canadian families with primary open-angle glaucoma (POAG). DESIGN: Family pedigree study. METHODS: A disease haplotype for the Q368STOP mutation of the myocilin gene has previously been identified in 15 Tasmanian families with POAG. The four microsatellite markers that constitute this 0.14-megabase (Mb) disease haplotype were genotyped in individuals from a large French Canadian family with POAG (family CT) and two unrelated French Canadian individuals with ocular hypertension. RESULTS: The Tasmanian Q368STOP disease haplotype was identified in affected individuals from family CT, and the same alleles were shared at the four microsatellite markers in the two unrelated French Canadian individuals. CONCLUSION: The same disease haplotype for the Q368STOP mutation of the myocilin gene was found in both the Tasmanian and French Canadian populations, supporting the view that this mutation arose from a common Caucasian founder.

Australia↗
PubMed2005

Post-cycloplegia myopic shift in an older population.

PURPOSE: To demonstrate that use of a mydriatic agent remains a significant confounder in autorefraction of the presbyopic population. METHODS: The pre- and post-cycloplegic autorefraction results of 37 subjects over 50 years of age were measured using a Humphrey-598 autorefractor. The results of both eyes were included in a multivariate regression analysis. RESULTS: The average age of the patient sample was 63.4 years. The mean spherical equivalent (SEQ) shifts for the hyperopic, myopic, pseudophakic, and emmetropic eyes were -0.53 D (95% CI -0.77 D to -0.39 D; p < 0.001), -0.38 D (95%CI -0.81 D to +0.04 D; p = 0.077), -0.49 D (95% CI -0.78 D to -0.20 D; p = 0.001), and -0.35 D (95% CI -0.59 D to -0.11 D; p = 0.004), respectively. CONCLUSION: Cyclopleged autorefraction in the presbyopic population is associated with a myopic shift that can potentially lead to overestimation of myopic prevalence. This is an important factor in comparing population studies where cyclogleged autorefraction is used in contrast to non-cyclopleged autorefraction and subjective refraction.

Accommodation, Ocular↗
PubMed2005

Chromosomal abnormalities and glaucoma: a case of congenital glaucoma with trisomy 8q22-qter/ monosomy 9p23-pter.

PURPOSE: To present a case of congenital glaucoma with an unbalanced translocation trisomy 8q22-qter/monosomy 9p23-pter, resulting in trisomy of the GLC1D locus. To perform a literature review of chromosomal abnormalities associated with glaucoma. METHOD: A case report of a family with balanced translocation without glaucoma and unbalanced translocation with congenital glaucoma. PubMed and OMIM databases were searched for reports of chromosomal abnormalities and glaucoma. RESULTS: Other case reports of congenital glaucoma with chromosomal abnormalities in this region were identified. A review of cytogenetics in southeastern Australia found nine cases involving the loss of 9p23 and 10 cases involving mosaicism for trisomy 8, but none had congenital glaucoma. A review of the literature identified reports of glaucoma and chromosomal abnormalities in regions with glaucoma loci mapped by conventional linkage analysis. These include the loci GLC1B, GLC1C, GLC1D, GLC1F, GPDS1, and RIEG2. CONCLUSION: The study of patients with glaucoma and chromosomal abnormalities may help to identify new glaucoma genes. Ophthalmologists can assist with this by requesting cytogenetic studies on congenital and developmental glaucoma cases and interacting with ophthalmic genetics researchers.

Adolescent↗
PubMed2005

Genotypic and phenotypic spectrum of X-linked retinoschisis in Australia.

BACKGROUND: X-linked retinoschisis (XLRS), an X-linked recessive inherited degenerative retinopathy, is characterized by splitting in the nerve fibre layer and is caused by alterations in the RS1 gene. The aim of the present study was to review both the phenotypic features of XLRS and the mutation spectrum of the RS1 gene in an Australian cohort. METHODS: Patients were recruited from ophthalmic and paediatric hospitals as well as private ophthalmic clinics across Australia. A cohort of 18 presumably unrelated families was identified. Twenty-two affected patients underwent clinical examination. Following DNA extraction all six exons of the RS1 gene were sequenced. RESULTS: The median age at diagnosis was 8 years (range 1-43 years); the median age at review was 14 years (range 5-63 years). The median best-corrected visual acuity upon review was 6/24 (range 6/6-1/36). Typical foveal schisis was found in 90.1% eyes examined (39/43) while peripheral schisis was present in 30% of eyes (13/43). The scotopic blue b-wave amplitude ranged between 2% and 82% of the mean normal amplitude. Five novel mutations (61G-->T, Gly21X; 103C-->T, Gln35X; 327-329del, Cys110del; 527T-->C, Phe176Ser; 573Gdel, Pro192fs) and six previously identified missense mutations (304C-->T, Arg102Trp; 305G-->A, Arg102Gln; 336G-->C, Trp112Cys; 418G-->A, Gln140Arg; 598C-->T, Arg200Cys; 625C-->T, Arg209Cys) were found. The mutations present in codons 21 and 102 were each identified in two presumably unrelated pedigrees. One previously described point deletion (416Adel) was identified. Two pedigrees contained affected individuals where exons 2 or 3, respectively, were unable to be amplified, indicating the likely presence of a significant deletion. No mutation was found in the RS1 gene in two affected individuals from different pedigrees. CONCLUSION: Population genetic studies of XLRS have not previously been conducted in Australia. The phenotype associated with these mutations varied. The identification of each pedigree's specific mutation allows future determination of female carrier status for genetic counselling purposes. Further study into the refinement of the XLRS phenotype as well as the degree of intrafamilial phenotypic variation is required.

Adolescent↗
PubMed2005

Central corneal thickness is highly heritable: the twin eye studies.

PURPOSE: A classic twin study was performed to determine the heritability of central corneal thickness (CCT), an important parameter in glaucoma assessment. METHODS: The concordance of CCT between monozygotic (MZ) and dizygotic (DZ) twins was compared. A total of 256 twin pairs (131 MZ and 125 DZ) were recruited from three centers: the Twin Eye Study in Tasmania, the Brisbane Adolescent Twin Study, and the Twins U.K. Adult Registry held at St. Thomas' Hospital in London. As part of an extensive ophthalmic evaluation, CCT was measured by ultrasound pachymetry. Structural equation modeling with the Mx program (Department of Psychiatry, Medical College of Virginia, Richmond, VA) was used to determine the heritability of CCT. RESULTS: The mean age of subjects was 38 years (range, 8-81). The mean CCT of all eyes examined was 544.5 +/- 37.3 mum (SD). The CCT measurements correlated more highly in MZ twins than in DZ twins, with intraclass correlation coefficients of 0.95 and 0.52, respectively, suggesting a strong genetic influence. A model of additive genetic and unique environmental effects provided the best fit, yielding a heritability of 0.95 (95% confidence interval [CI], 0.93-0.96) with the remaining variation being attributable to unique environmental factors. CONCLUSIONS: In this study of Australian and U.K. twins, genetic factors were shown to be of major importance in CCT, with a heritability of 0.95.

Adolescent↗
PubMed2005

Linkage to 10q22 for maximum intraocular pressure and 1p32 for maximum cup-to-disc ratio in an extended primary open-angle glaucoma pedigree.

PURPOSE: The purpose of this study was to identify genetic contributions to primary open-angle glaucoma (POAG) through investigations of two quantitative components of the POAG phenotype. METHODS: Genome-wide multipoint variance-components linkage analyses of maximum recorded intraocular pressure (IOP) and maximum vertical cup-to-disc ratio were conducted on data from a single, large Australian POAG pedigree that has been found to segregate the myocilin Q368X mutation in some individuals. RESULTS: Multipoint linkage analysis of maximum recorded IOP produced a peak LOD score of 3.3 (P = 0.00015) near marker D10S537 on 10q22, whereas the maximum cup-to-disc ratio produced a peak LOD score of 2.3 (P = 0.00056) near markers D1S197 to D1S220 on 1p32. Inclusion of the myocilin Q368X mutation as a covariate provided evidence of an interaction between this mutation and the IOP and cup-to-disc ratio loci. CONCLUSIONS: Significant linkage has been identified for maximum IOP and suggestive linkage for vertical cup-to-disc ratio. Identification of genes contributing to the variance of these traits will enhance understanding of the pathophysiology of POAG as a whole.

Chromosomes, Human, Pair 1↗
PubMed2004

Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q.

Familial exudative vitreoretinopathy (FEVR) is an inherited blinding disorder of the retinal vascular system. Autosomal dominant FEVR is genetically heterogeneous, but its principal locus, EVR1, is on chromosome 11q13-q23. The gene encoding the Wnt receptor frizzled-4 (FZD4) was recently reported to be the EVR1 gene, but our mutation screen revealed fewer patients harboring mutations than expected. Here, we describe mutations in a second gene at the EVR1 locus, low-density-lipoprotein receptor-related protein 5 (LRP5), a Wnt coreceptor. This finding further underlines the significance of Wnt signaling in the vascularization of the eye and highlights the potential dangers of using multiple families to refine genetic intervals in gene-identification studies.

Amino Acid Sequence↗
PubMed2004

Primary infantile glaucoma in an Australian population.

BACKGROUND: Primary infantile glaucoma presents rarely, but can be responsible for significant visual morbidity. There is little information on the clinical features and visual outcome of a pure population of primary infantile glaucoma, as opposed to a mixed population of primary and secondary glaucoma or combined group of those with trabeculodysgenesis and iridotrabeculodysgenesis. METHODS: We conducted a retrospective review of children with primary infantile glaucoma seen in south-eastern Australia between 1980 and 2000, using The Royal Children's Hospital ophthalmic diagnostic coding database. RESULTS: Fifty-one patients with primary infantile glaucoma were identified (83 eyes). This equates to an estimated incidence of approximately 1 in 30,000 births. The mean +/- SD age at presentation was 135 +/- 84 days. 'Burnt-out' disease (megalocornea without raised intraocular pressure) was diagnosed in 10.8%. Goniotomy was the most commonly performed surgical procedure (69.4% of 72 eyes). Surgical success with one or two goniotomies was achieved in 74% of eyes. Visual outcomes at final review were generally good with 61.8% reading 6/12 or better. There were a disproportionately high number of children having a final recorded acuity of <6/60 in the group diagnosed in the first 3 months of life. CONCLUSIONS: Primary infantile glaucoma is a rare ocular condition in this population that presents at a mean age of 4.4 months. Surgical and visual outcomes are generally favourable.

Age Distribution↗
PubMed2004

Are Duane syndrome and infantile esotropia allelic?

PURPOSE: To evaluate the clinical overlap of families with Duane syndrome and infantile esotropia to determine whether the identification of genes for Duane syndrome may explain some cases of infantile esotropia. METHODS: Three separate groups of patients were evaluated. 1) Families with features of infantile esotropia were identified through the Strabismus Inheritance Study Tasmania (SIST). Clinical details of participants and their families were reviewed for any cases of Duane syndrome. 2) Cases of Duane syndrome were identified through the clinical diagnostic database at the Royal Children's Hospital, Melbourne, and private ophthalmology clinics in Melbourne and Tasmania. Previous medical notes were reviewed and family history of strabismus noted. All affected individuals were invited for re-examination in cases where a positive family history of strabismus was reported; siblings, parents, and other family members, where appropriate, were invited to be examined for signs of Duane syndrome or infantile esotropia. 3) Cases of mosaic trisomy 8, which has been associated with Duane syndrome and infantile esotropia, were reviewed for signs of strabismus. RESULTS: A total of 133 families from the SIST were reviewed, but no 'pure' families of Duane syndrome were identified. Two families with infantile esotropia had several members affected with Duane syndrome. Of the 40 index cases with Duane syndrome whose families agreed to be involved in the study, 21 had a family history of ocular motility disorders, but only two of these families had multiple cases of Duane syndrome. From 24 cases with mosaic trisomy 8, one individual case had Duane syndrome and another had mild congenital cataracts and infantile esotropia. CONCLUSIONS: There is clinical overlap in families with Duane syndrome and infantile esotropia. We confirmed the previous association of mosaic trisomy 8 with both Duane syndrome and infantile esotropia. These data suggest that the two conditions may be allelic and may be due to a gene on chromosome 8.

Alleles↗
PubMed2004

Attitudes to predictive DNA testing for myocilin glaucoma: experience with a large Australian family.

PURPOSE: Glaucoma is a major cause of visual impairment and blindness in developed countries. Half of those with glaucoma are unaware that they have the disease. Mutations in the myocilin (MYOC) gene are responsible for 3 to 5% of primary open angle glaucoma, thus predictive DNA testing in family members of some glaucoma pedigrees is possible. We wished to determine the attitudes of affected and unaffected family members to the use of predictive DNA testing in glaucoma. SUBJECTS AND METHODS: We surveyed the attitudes of family members from one such pedigree to determine the acceptability of predictive DNA testing. We studied 72 members of a large family in which the MYOC mutation, THR377MET, segregates. Family members were examined over an 8-year period as part of research initiated to identify the gene. Once the mutation was identified, we offered participants the result of their DNA test after a genetic counseling session. Family members were subsequently given a questionnaire about the counseling and DNA result. RESULTS: Most wished to know their result after counseling; 26 of 27 (96%) felt the genetic counseling session was necessary, but participants' attitudes varied as to whether they preferred this in person, by phone, or letter. Forty three patients were resurveyed 5 years after their initial counseling session. No adverse problems relating to the predictive testing were reported, though two had been asked about DNA testing by insurance companies; 5 of 24 (21%) individuals who had been informed they did not carry the mutation were unsure if they carried the mutation 5 years after counseling, while all 19 mutation carriers (who were being examined annually) correctly recalled their mutation status. CONCLUSIONS: This study suggests that predictive glaucoma testing in appropriate circumstances is acceptable to patients and their families.

Attitude to Health↗
PubMed2004

Analysis of optineurin (OPTN) gene mutations in subjects with and without glaucoma: the Blue Mountains Eye Study.

BACKGROUND: The optineurin (OPTN) gene has been reported to possess both causal as well as risk-associated alleles for open-angle glaucoma. However, these findings have so far only been reported in family and clinic based studies. The aim of this study was to investigate the spectrum of mutations and gene variants in OPTN that might be present in people with glaucoma from a population-based study, the Blue Mountains Eye Study (BMES). METHODS: A total of 108 subjects of Caucasian origin were identified at baseline in the BMES as having open-angle glaucoma. Blood samples were available from 27 of these, of whom 18 had high-tension glaucoma and the remaining nine had normal-tension glaucoma. Ninety-four control subjects were chosen at random from the BMES, who satisfied the criteria of not having glaucoma at baseline and were over age 70 years. The 13 coding exons (exons 4-16 inclusive) and their intron-exon boundaries of OPTN were screened by the use of single-strand conformation polymorphism. Samples exhibiting mobility shifts were di-deoxy nucleotide sequenced. The M98K polymorphism was additionally screened using the restriction enzyme Stu1 in all cases and controls in this study. RESULTS: The M98K risk-associated alteration was identified in 2/18 (11%) subjects with high-tension glaucoma, 0/9 subjects (0%) with normal-tension glaucoma and 3/94 (3.2%) controls. However, association of this variant with disease was not significant (P = 0.2 for each phenotype) for either high-tension glaucoma or normal-tension glaucoma. A novel variant (P556P in exon 16) was found in one subject with open-angle glaucoma and a previously described variant (exon 7) was found in a further subject with open-angle glaucoma and in one control. No other OPTN variants were identified in this study cohort. CONCLUSIONS: Cross-sectional analysis from baseline observations of the BMES suggested that the M98K risk-associated allele appeared at a higher prevalence in high-tension glaucoma compared with controls, although this finding was not statistically significant.

Aged↗
PubMed2004

Spectrum and frequency of FZD4 mutations in familial exudative vitreoretinopathy.

PURPOSE: Mutations in the frizzled-4 gene (FZD4) have recently been associated with autosomal dominant familial exudative vitreoretinopathy (FEVR) in families linking to the EVR1 locus on the long arm of chromosome 11. The purpose of this study was to screen FZD4 in a panel of 40 patients with FEVR to identify the types and location of mutations and to calculate what proportion of this heterogeneous condition is attributable to FZD4 mutations. METHODS: PCR products were generated from genomic DNA with primers designed to amplify the coding sequence of FZD4. The PCR products were screened for mutations by single-strand conformational polymorphism-heteroduplex analysis (SSCP-HA) and by direct sequencing. RESULTS: In total, eight mutations were identified, seven of which were novel. Three were deletions (c957delG, c1498delA, and c1501-1502delCT), one was a nonsense mutation (Q505X), and four were missense mutations (G36D, M105T, M157V, and S497F). CONCLUSIONS: Eight mutations have been identified in the FZD4 gene in a cohort of 40 unrelated patients with FEVR. This result indicates that FZD4 mutations are responsible for only 20% of FEVR index cases and suggests that the other FEVR loci may account for more cases than previously anticipated.

Adult↗
PubMed2004

Identification of KIF21A mutations as a rare cause of congenital fibrosis of the extraocular muscles type 3 (CFEOM3).

PURPOSE: Three congenital fibrosis of the extraocular muscles phenotypes (CFEOM1-3) have been identified. Each represents a specific form of paralytic strabismus characterized by congenital restrictive ophthalmoplegia, often with accompanying ptosis. It has been demonstrated that CFEOM1 results from mutations in KIF21A and CFEOM2 from mutations in PHOX2A. This study was conducted to determine the incidence of KIF21A and PHOX2A mutations among individuals with the third CFEOM phenotype, CFEOM3. METHODS: All pedigrees and sporadic individuals with CFEOM3 in the authors' database were identified, whether the pedigrees were linked or consistent with linkage to the FEOM1, FEOM2, and/or FEOM3 loci was determined, and the appropriate pedigrees and the sporadic individuals were screened for mutations in KIF21A and PHOX2A. RESULTS: Twelve CFEOM3 pedigrees and 10 CFEOM3 sporadic individuals were identified in the database. The structures of eight of the pedigrees permitted the generation of meaningful linkage data. KIF21A was screened in 17 probands, and mutations were identified in two CFEOM3 pedigrees. One pedigree harbored a novel mutation (2841G-->A, M947I) and one harbored the most common and recurrent of the CFEOM1 mutations identified previously (2860C-->T, R954W). None of CFEOM3 pedigrees or sporadic individuals harbored mutations in PHOX2A. CONCLUSIONS: The results demonstrate that KIF21A mutations are a rare cause of CFEOM3 and that KIF21A mutations can be nonpenetrant. Although KIF21A is the first gene to be associated with CFEOM3, the results imply that mutations in the unidentified FEOM3 gene are the more common cause of this phenotype.

DNA Mutational Analysis↗
PubMed2003

Investigation of albinism genes in congenital esotropia.

PURPOSE: Esotropia is a feature of albinism. Amongst esotropic patients there may be mild unrecognised albinos. Oculocutaneous albinism shares several clinical features with congenital esotropia. It is well known that mammals with oculocutaneous albinism have misrouted retinal ganglion cell axons, most likely caused by the absence of melanin or DOPA during development. We investigated the hypothesis that mutations in the albinism genes Tyrosinase, the P Gene, and TYRP1 may also be responsible for congenital esotropia via a similar mechanism. METHODS: We screened these three genes in 21 families with congenital esotropia using single stranded conformational polymorphism analysis. RESULTS: No rare sequence variants segregating with esoptopia were detected. A novel silent mutation of the TYRP1 gene was identified in one pedigree but is not likely to be causative. Several previously reported common polymorphisms were detected but do not segregate with disease in this population. CONCLUSIONS: Rare mutations of these genes do not appear to be responsible for congenital esotropia. Although we found no evidence for segregation of common variants with disease, these require further investigation for a possible contribution to a complex threshold model. Several lines of evidence indicate a genetic componenet of congenital esotropia, however, this is the first investigation of candidate genes for this disorder.

Albinism, Oculocutaneous↗
PubMed2003

Mutations in a novel gene, NHS, cause the pleiotropic effects of Nance-Horan syndrome, including severe congenital cataract, dental anomalies, and mental retardation.

Nance-Horan syndrome (NHS) is an X-linked disorder characterized by congenital cataracts, dental anomalies, dysmorphic features, and, in some cases, mental retardation. NHS has been mapped to a 1.3-Mb interval on Xp22.13. We have confirmed the same localization in the original, extended Australian family with NHS and have identified protein-truncating mutations in a novel gene, which we have called "NHS," in five families. The NHS gene encompasses approximately 650 kb of genomic DNA, coding for a 1,630-amino acid putative nuclear protein. NHS orthologs were found in other vertebrates, but no sequence similarity to known genes was identified. The murine developmental expression profile of the NHS gene was studied using in situ hybridization and a mouse line containing a lacZ reporter-gene insertion in the Nhs locus. We found a complex pattern of temporally and spatially regulated expression, which, together with the pleiotropic features of NHS, suggests that this gene has key functions in the regulation of eye, tooth, brain, and craniofacial development.

Abnormalities, Multiple↗