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J L Wiggs

Publications and source records attributed to J L Wiggs.

At least 19 recordsLinked to original sources
PubMed2004

A genomewide scan identifies novel early-onset primary open-angle glaucoma loci on 9q22 and 20p12.

Glaucoma is a leading cause of blindness worldwide. The disease is characterized by a degeneration of the optic nerve, which is usually associated with elevated intraocular pressure. The common form of adult-onset primary open-angle glaucoma is inherited as a complex trait, whereas the rarer early-onset juvenile open-angle glaucoma (JOAG) exhibits autosomal dominant inheritance. Of all cases of JOAG, approximately 10%-20% are caused by mutations in the myocilin gene. We have identified 25 pedigrees that are affected with typical JOAG and that demonstrate autosomal dominant inheritance. We sequenced the myocilin gene in probands from each family and found mutations in 8% of this population. To identify novel genes responsible for JOAG, we used families that did not have myocilin mutations for a genomewide screen. Markers located on chromosomes 9q22 and 20p12 showed evidence for linkage, identifying two novel loci for early-onset open-angle glaucoma.

Age of Onset↗
PubMed2001

Molecular and clinical evaluation of a patient hemizygous for TIGR/MYOC.

OBJECTIVE: To determine if a patient with an interstitial deletion of chromosome 1 is hemizygous for the TIGR/MYOC gene and if that patient has glaucoma. METHODS: A patient with an interstitial deletion of chromosome 1 was clinically examined for evidence of glaucoma. DNA samples from the patient and her family were used for molecular studies to determine the boundaries of the chromosome 1 deletion using polymorphic markers located on chromosome 1q21 to 1q24. Additional markers located in the vicinity of the TIGR/MYOC gene, including 2 derived from the ends of the gene, were used to determine if it was included in the deletion. RESULTS: The patient and her family showed no evidence of glaucoma. Molecular analysis demonstrated that a complex deletion of the maternal copy of chromosome 1 included the entire TIGR/MYOC gene. CONCLUSIONS: We have determined that the patient has only 1 functional copy of TIGR/MYOC. The lack of clinical evidence of glaucoma suggests that haploinsufficiency of the TIGR/MYOC protein is not the cause of early-onset glaucoma associated with mutations in TIGR/MYOC. CLINICAL RELEVANCE: Missense and nonsense mutations in the TIGR/MYOC gene have been associated with juvenile- and adult-onset primary open-angle glaucoma. Although many different mutations have been correlated with the disease, the underlying genetic mechanism (haploinsufficiency, gain of function, or a dominant negative effect) remains unknown. Information regarding the genetic mechanism responsible for TIGR/MYOC-associated glaucoma is necessary for further studies designed to develop transgenic animal models and gene-related therapy.

Adult↗
PubMed2001

Molecular and clinical characterization of a patient with a chromosome 4p deletion, Wolf-Hirschhorn syndrome, and congenital glaucoma.

Wolf-Hirschhorn syndrome is a developmental disorder associated with hemizygous deletion of the distal short arm of chromosome 4. We have identified a patient affected with Wolf-Hirschhorn syndrome and early onset glaucoma. Five other patients with Wolf-Hirschhorn syndrome and early onset glaucoma or ocular anomalies associated with early onset glaucoma have been previously described, suggesting that the association with Wolf-Hirschhorn syndrome is not coincidental. The infrequent association of early onset glaucoma suggests that the chromosomal region commonly deleted in Wolf-Hirschhorn patients does not contain genes responsible for early onset glaucoma. In this study, we performed a molecular characterization of the deleted chromosome 4 to determine the extent of the deletion in an attempt to begin to identify the chromosomal region responsible for the associated glaucoma. Using microsatellite repeat markers located on 4p, we determined that the deletion spanned a 60-cM region including the minimal Wolf-Hirschhorn region. The proximal breakpoint occurred between markers D4S3045 and D4S2974. These results support the hypothesis that patients with Wolf-Hirschhorn syndrome and early onset glaucoma may have large deletions of 4p that include a gene(s) that may be responsible for a dominant form of congenital glaucoma.

Chromosome Deletion↗
PubMed2000

Genome-wide scan for adult onset primary open angle glaucoma.

Adult onset primary open angle glaucoma is a leading cause of blindness throughout the world. The disease results in an apoptotic death of retinal ganglion cells that is usually associated with an elevation of intraocular pressure. Familial aggregation of the disorder provides evidence for strong genetic influences that are likely to be the result of multiple susceptibility genes. A two-stage genome scan to identify the genomic locations of glaucoma susceptibility genes was performed using an initial pedigree set of 113 affected sibpairs and a second pedigree set of 69 affected sibpairs. Linkage analysis was performed using both model-dependent (lod score) and model-independent affected relative pair and sibpair methods. Twenty-five regions identified by the initial scan were further investigated using the second pedigree set. In the combined data analysis, regions located on chromosomes 2, 6, 9, 11, 14, 17 and 19 continued to produce model-dependent lod scores and/or an MLS >1.0, while five regions (2, 14, 17p, 17q and 19) produced an MLS >2. 0. Multipoint analysis using ASPEX also showed significant results on chromosomes 2, 14, 17p, 17q and 19. These results are an important step towards the identification of genes responsible for the genetic susceptibility to this blinding condition.

Age of Onset↗
PubMed1999

Role of genetic factors in the etiology of juvenile-onset myopia based on a longitudinal study of refractive error.

In an attempt to determine the role of genetic factors in the development of myopia, we examined the relationship of infantile refractive error and parental history to juvenile-onset myopia and analyzed 43 pedigrees affected by juvenile-onset myopia. Refraction data collected at regular intervals from a sample of juvenile subjects participating in a 24-year longitudinal study of refractive error were used. Results showed that children with two myopic parents were 6.42 times as likely to become myopic as children with one or no myopic parents. Furthermore, children who had refractions in the lower half of the distribution at 6 to 12 months of age were 4.33 times as likely to develop myopia as children who had refractions in the upper half of the distribution at 6 to 12 months of age. The pedigree analysis indicated that 63% of individuals considered at risk for developing juvenile-onset myopia actually became myopic, with an equal number of affected males and females. These results suggest that juvenile-onset myopia of moderate amounts may be inherited as a complex trait involving both genetic and environmental factors.

Adolescent↗
PubMed1998

Gln368STOP myocilin mutation in families with late-onset primary open-angle glaucoma.

PURPOSE: To examine families ascertained for late-onset primary open-angle glaucoma (POAG) to determine mutations in the gene coding for myocilin. METHODS: The diagnosis of late-onset POAG was defined as age at diagnosis more than 35 years, intraocular pressure (IOP) 22 mm Hg or more in both eyes or 19 mm Hg or more while the patient was taking two glaucoma medications, glaucomatous optic neuropathy in both eyes, and visual field loss consistent with optic nerve damage in at least one eye of the proband. Two of three criteria were required in other family members. DNA from all families was screened for polymorphisms in myocilin using single-strand conformation polymorphism analysis. All polymorphisms were sequenced for mutations. RESULTS: Eighty-three affected people in 29 families with late-onset POAG were screened for mutations. Three mutations, two novel missense (Thr377Met and Glu352Lys) and one nonsense (Gln368STOP), were identified. The missense mutations did not segregate with the disease phenotype in these families. The nonsense mutation was found in 3 of 29 unrelated families with POAG. All affected family members and 8 of 12 in whom glaucoma was suspected had the Gln368STOP mutation. All people with this mutation had elevated IOP, and 78% had POAG by age 70. CONCLUSIONS: Three mutations were identified in the gene coding for myocilin in families with late-onset POAG. Of these, the Gln368STOP mutation was highly associated with the development of glaucoma. All people with this mutation had glaucoma or elevated IOP by age 70. In the United States, the Gln368STOP mutation in myocilin is strongly associated with the development of late-onset POAG. However, factors in addition to the presence of this mutation seem to play a role in the development of ocular hypertension and glaucoma in these families.

Adult↗
PubMed1997

A gene responsible for the pigment dispersion syndrome maps to chromosome 7q35-q36.

OBJECTIVES: To demonstrate the inheritance of the pigment dispersion syndrome in 4 families and to determine the location of a gene responsible for this syndrome. PATIENTS: Fifty-four members of 4 families affected by the pigment dispersion syndrome and pigmentary glaucoma. All 4 families are white. Two of the pedigrees are of Irish descent, and 2 are of mixed western European descent that includes some Irish ancestry. INTERVENTIONS: Individuals from 4 pedigrees affected by the pigment dispersion syndrome and their spouses were clinically examined for evidence of the pigment dispersion syndrome. DNA samples from patients and appropriate family members were used for a genome screen using microsatellite repeat markers distributed throughout the human genome. Genotypes were used for linkage analysis to identify markers segregating with the disease trait. RESULTS: Twenty-eight patients showed clinical evidence of the pigment dispersion syndrome. Of these, 14 also had elevated intraocular pressures requiring medical or surgical treatment or both. Significant linkage was observed between the disease phenotype and markers located on the telomere of the long arm of human chromosome 7 (i.e., 7q35-q36). The maximum 2-point lod score (i.e., Zmax) for a single pedigree (i.e., PDS5) was 5.72 at theta = 0 for markers D7S2546 and D7S550. An analysis of affected recombinant individuals demonstrated that the responsible gene is located in a 10-centimorgan interval between markers D7S2462 and D7S2423. CONCLUSIONS: The pigment dispersion syndrome was found to be inherited as an autosomal dominant trait in 4 affected pedigrees. The gene responsible for the syndrome in these 4 families maps to the telomeric end of the long arm of chromosome 7 (i.e., 7q35-q36). Locating a gene responsible for this condition is the first step toward the isolation of the gene itself. Characterization of the responsible gene will help elucidate the pathophysiology of this disease and potentially will lead to new methods of diagnosis and treatment.

Adolescent↗
PubMed1996

A second locus for Rieger syndrome maps to chromosome 13q14.

Rieger syndrome is a genetically and phenotypically heterogeneous disorder typically characterized by malformations of the eyes, teeth, and umbilicus. The syndrome is inherited as an autosomal dominant trait and exhibits significant variable expressivity. One locus associated with this disorder has been mapped to 4q25. Using a large four-generation pedigree, we have identified a second locus for Rieger syndrome located on chromosome 13q14.

Abnormalities, Multiple↗
PubMed1995

Clinical features of five pedigrees genetically linked to the juvenile glaucoma locus on chromosome 1q21-q31.

BACKGROUND: Primary juvenile glaucoma is a rare form of glaucoma that typically affects individuals between 3 and 20 years of ages and is inherited as an autosomal dominant trait. One gene responsible for this condition has been localized to the 1q21-q31 region of chromosome 1. To investigate the clinical features of this form of glaucoma, the authors have examined the affected members of five pedigrees demonstrating genetic linkage to the 1q21-q31 locus. METHODS: Clinical characterization of 23 affected patients was performed. Genetic linkage to the 1q21-q31 locus was confirmed by segregation of the disease trait in each pedigree with genetic markers located in the 1q21-q31 region. RESULTS: The clinical features of affected members of the five pedigrees presented are generally homogeneous. The average age of diagnosis was 18.5 years (range, 5-30 years), and the average initial intraocular pressure was 38.5 mmHg (range, 30-53 mmHg). Eighty-seven percent of affected individuals were myopic and 83% of affected individuals required surgical treatment for glaucoma. There were no uniformly associated systemic or ocular conditions. One possible nonpenetrant carrier was identified and a difference in phenotypic expression of the presumed disease gene was observed in a pair of affected monozygotic twins. We also identified two pedigrees with juvenile glaucoma and three pedigrees affected by the pigment dispersion syndrome that are not genetically linked to the 1q21-q31 region. CONCLUSION: The form of juvenile glaucoma caused by a gene located in the q21-q31 region of chromosome 1 is generally phenotypically homogeneous. The severe elevation of intraocular pressure typically seen in affected patients suggests the product of the predisposing gene may participate in the outflow function of the eye.

Adolescent↗
PubMed1994

Genetic linkage of autosomal dominant juvenile glaucoma to 1q21-q31 in three affected pedigrees.

Glaucoma is a common disorder that results in irreversible damage to the optic nerve, causing absolute blindness. In most cases, the optic nerve is damaged by an elevation of the intraocular pressure that is the result of an abnormality in the normal drainage function of the trabecular meshwork. A family history of glaucoma is an important risk factor for the disease, suggesting that genetic defects predisposing to this condition are likely. Three pedigrees segregating an autosomal dominant juvenile glaucoma demonstrated significant linkage to a group of closely spaced markers on chromosome 1. These results confirm the initial mapping of this disease and suggest that this region on chromosome 1 contains an important locus for juvenile glaucoma. We describe recombination events that improve the localization of the responsible gene, reducing the size of the candidate region from 30 to 12 cM.

Adult↗