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Thomas Rosenberg

Publications and source records attributed to Thomas Rosenberg.

At least 19 recordsLinked to original sources
PubMed2007

Transgenic mice carrying the H258N mutation in the gene encoding the beta-subunit of phosphodiesterase-6 (PDE6B) provide a model for human congenital stationary night blindness.

Mutations in the beta-subunit of cGMP-phosphodiesterase (PDE6beta) can lead to either progressive retinal disease, such as human retinitis pigmentosa (RP), or stationary disease, such as congenital stationary night blindness (CSNB). Individuals with CSNB in the Rambusch pedigree were found to carry the H258N allele of PDE6B (MIM# 180072); a similar mutation was not found in RP patients. This report describes an individual carrying the H258N allele, who presented with generalized retinal dysfunction affecting the rod system and a locus of dysfunction at the rod-bipolar interface. Also described are preclinical studies in which transgenic mice with the H258N allele were generated to study the pathophysiological mechanisms of CSNB. While Pde6b(rd1)/Pde6b(rd1) mice have severe photoreceptor degeneration, as in human RP, the H258N transgene rescued these cells. The cGMP-PDE6 activity of dark-adapted H258N mice showed an approximate three-fold increase in the rate of retinal cGMP hydrolysis: from 130.1 nmol x min(-1) x nmol(-1) rhodopsin in wild-type controls to 319.2 nmol x min(-1) x nmol(-1) rhodopsin in mutants, consistent with the hypothesis that inhibition of the PDE6beta activity by the regulatory PDE6gamma subunit is blocked by this mutation. In the albino (B6CBA x FVB) F2 hybrid background, electroretinograms (ERG) from H258N mice were similar to those obtained from affected Rambusch family members, as well as humans with the most common form of CSNB (X-linked), demonstrating a selective loss of the b-wave with relatively normal a-waves. When the H258N allele was introduced into the DBA background, there was no evidence of selective reduction in b-wave amplitudes; rather a- and b-wave amplitudes were both reduced. Thus, factors other than the PDE6B mutation itself could contribute to the variance of an electrophysiological response. Therefore, caution is advisable when interpreting physiological phenotypes associated with the same allele on different genetic backgrounds. Nevertheless, such animals should be of considerable value in further studies of the molecular pathology of CSNB.

Adult↗
PubMed2006

Development of a genotyping microarray for Usher syndrome.

BACKGROUND: Usher syndrome, a combination of retinitis pigmentosa (RP) and sensorineural hearing loss with or without vestibular dysfunction, displays a high degree of clinical and genetic heterogeneity. Three clinical subtypes can be distinguished, based on the age of onset and severity of the hearing impairment, and the presence or absence of vestibular abnormalities. Thus far, eight genes have been implicated in the syndrome, together comprising 347 protein-coding exons. METHODS: To improve DNA diagnostics for patients with Usher syndrome, we developed a genotyping microarray based on the arrayed primer extension (APEX) method. Allele-specific oligonucleotides corresponding to all 298 Usher syndrome-associated sequence variants known to date, 76 of which are novel, were arrayed. RESULTS: Approximately half of these variants were validated using original patient DNAs, which yielded an accuracy of >98%. The efficiency of the Usher genotyping microarray was tested using DNAs from 370 unrelated European and American patients with Usher syndrome. Sequence variants were identified in 64/140 (46%) patients with Usher syndrome type I, 45/189 (24%) patients with Usher syndrome type II, 6/21 (29%) patients with Usher syndrome type III and 6/20 (30%) patients with atypical Usher syndrome. The chip also identified two novel sequence variants, c.400C>T (p.R134X) in PCDH15 and c.1606T>C (p.C536S) in USH2A. CONCLUSION: The Usher genotyping microarray is a versatile and affordable screening tool for Usher syndrome. Its efficiency will improve with the addition of novel sequence variants with minimal extra costs, making it a very useful first-pass screening tool.

DNA↗
PubMed2006

The congenital "ant-egg" cataract phenotype is caused by a missense mutation in connexin46.

PURPOSE: "Ant-egg" cataract is a rare, distinct variety of congenital/infantile cataract that was reported in a large Danish family in 1967. This cataract phenotype is characterized by ant-egg-like bodies embedded in the lens in a laminar configuration and is inherited as an autosomal dominant trait. We retrieved the family and performed linkage analysis to determine the disease locus and identify the mutated gene. METHODS: The family (CC00103) was identified in a National Register of Hereditary Eye Diseases and updated based on The Danish Civil Register System. Genome wide linkage analysis and haplotyping using STS marker systems were carried out to achieve a LOD score above 3. The disease-causing candidate gene was sequenced and the mutation was identified and verified by restriction enzyme digestion of genomic DNA from all individuals in family CC00103 and 60 healthy controls. RESULTS: Linkage analysis resulted in a LOD score of 3.91 for marker D13S1275 located close to the known cataract gene GJA3. A novel missense mutation c.32T > C (L11S), was found by sequencing DNA from two affected members. The mutation was present in all affected individuals and was neither found in unaffected family members nor in 60 healthy individuals by restriction enzyme digests. CONCLUSIONS: The congenital "ant-egg" cataract phenotype is caused by a L11S mutation in connexin46 (Cx46) located in the signal peptide domain. Further studies are needed to unravel the mechanism leading to the formation of the "ant-eggs".

Amino Acid Sequence↗
PubMed2005

CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia.

Achromatopsia is a congenital, autosomal recessively inherited disorder characterized by a lack of color discrimination, low visual acuity (<0.2), photophobia, and nystagmus. Mutations in the genes for CNGA3, CNGB3, and GNAT2 have been associated with this disorder. Here, we analyzed the spectrum and prevalence of CNGB3 gene mutations in a cohort of 341 independent patients with achromatopsia. In 163 patients, CNGB3 mutations could be identified. A total of 105 achromats carried apparent homozygous mutations, 44 were compound (double) heterozygotes, and 14 patients had only a single mutant allele. The derived CNGB3 mutation spectrum comprises 28 different mutations including 12 nonsense mutations, eight insertions and/or deletions, five putative splice site mutations, and three missense mutations. Thus, the majority of mutations in the CNGB3 gene result in significantly altered and/or truncated polypeptides. Several mutations were found recurrently, in particular a 1 bp deletion, c.1148delC, which accounts for over 70% of all CNGB3 mutant alleles. In conclusion, mutations in the CNGB3 gene are responsible for approximately 50% of all patients with achromatopsia. This indicates that the CNGB3/ACHM3 locus on chromosome 8q21 is the major locus for achromatopsia in patients of European origin or descent.

Alleles↗
PubMed2005

Mutation analysis of the WFS1 gene in seven Danish Wolfram syndrome families; four new mutations identified.

Wolfram syndrome (WS) is a neuro-degenerative autosomal recessive (AR) disorder (OMIM #222300) caused by mutations in the WFS1 gene on 4p16.1. More than 120 mutations have been identified in WFS1 associated with AR WS, as well as autosomal dominant nonsyndromic low-frequency sensorineural hearing loss (LFSNHL). WFS1 variants were identified in eight subjects from seven families with WS, leading to the identification of four novel mutations, Q194X (nonsense), H313Y (missense), L313fsX360 (duplication frame shift) and F883fsX951 (deletion frame shift), and four previously reported mutations, A133T and L543R (missense), V415del (in frame triple deletion) and F883fsX950 (deletion frame shift). A mutation was found in 11/14 disease chromosomes, two subjects were homozygous for one mutation, one subject was compound heterozygous for two nucleotide substitutions (missense), one subject was compound heterozygous for a duplication and a deletion (frame shift), and in three families only one mutation was detected (Q194X and H313Y). All affected individuals shared clinically early-onset diabetes mellitus and progressive optic atrophy with onset in the first and second decades, respectively. In contrast, diabetes insipidus was present in two subjects only. Various degrees and types of hearing impairment were diagnosed in six individuals and cataract was observed in five subjects.

Adolescent↗
PubMed2005

Hereditary high hypermetropia in the Faroe Islands.

PURPOSE: To characterize the phenotype of two families with high hypermetropia from the Faroe Islands. METHODS: Ophthalmologic evaluation including ultrasound oculometry and anthropometric measurements. RESULTS: Of the 40 examined family members, 15 individuals (8 males, 7 females; ages: 6-77 years; mean: 36.5 years) had small deep-set eyes with high hypermetropia (median: + 16.5 D; range: + 7.75 to + 22), short axial eye length (< 21 mm), and a thickened eye wall. The median corrected visual acuity was 0.4 (0.2-0.9). Ocular complications included angle-closure glaucoma in six eyes, uveal effusion in three eyes, cataract in two eyes, and esotropia with amblyopia in three eyes. An emergency case of uveal effusion and retinal detachment after Yag iridotomy eventually responded to systemic corticosteroids and scleral resection surgery with a slow visual recovery. No associated ocular or systemic malformations were found in the series. In addition to the two examined families, six smaller Faroese families with high hypermetropia are briefly reported. CONCLUSIONS: The study highlights the signs and symptoms of a rare hereditary phenotype characterized by a short axial length mainly confined to the posterior segment of the eye, a shallow anterior chamber, and a thickened eye wall. The morphological characteristics predispose for sight-threatening complications such as angle-closure glaucoma, chorioretinal pathology including uveal effusion, and amblyopia. Regular ophthalmic follow-up is therefore of obvious importance in families known to have small eyes/high hypermetropia. An endemic high prevalence in the Faroe Islands suggests the presence of a founder effect, and further genetic research would probably indicate pseudodominant rather than dominant transmission

Adolescent↗
PubMed2005

Nordic research in ophthalmology.

Nordic ophthalmologists and vision scientists are active in many fields of eye research. This is most evident at the biannual Nordic Congress of Ophthalmology, most recently held in Malmö in June 2004. The authors here review some of the research in vision and ophthalmology presented at this meeting or published recently by Nordic scientists. This paper does not represent a comprehensive review of all Nordic research in the field, but attempts to give an overview of some of the activities underway in eye research in this part of the world.

Animals↗
PubMed2005

Risk factors for idiopathic congenital/infantile cataract.

PURPOSE: To investigate maternal, demographic, and pre- and perinatal risk factors for idiopathic congenital/infantile (ICI) cataract. METHODS: Based on national registries, a cohort of all children born in Denmark and aged 0 to 17 years during 1977 to 2001 was established, and congenital/infantile cataract cases were identified. Cases of unknown/idiopathic cause were included in the study. Associations between maternal, demographic, and pre- and perinatal factors with the development of cataract were investigated. RESULTS: In a cohort of 2.9 million children, 1027 cases of congenital/infantile cataract were identified. Of the children in those cases, 629 were born in Denmark and had ICI. Bilateral isolated cataract cases were male dominated (62%; 95% confidence interval [CI], 56%-69%) but not unilateral isolated cases (40%; 95% CI, 34%-47%). Older age (> or =40 years) of mothers at delivery and caesarean section increased the risk of ICI cataract. Low birth weight (< 2000 g) was associated with a 10.6-fold (95% CI, 6.99-16.10) increased risk of bilateral, but not unilateral, ICI cataract. No significant associations were found with birth order, month/place of birth, or cigarette smoking during pregnancy. CONCLUSIONS: Variables indicative of environmental influence were not associated with ICI cataract. Low-birth-weight children (< 2000 g) had a significantly increased risk of bilateral ICI, whereas no strong risk factors were found for unilateral cataract. Together with the sex difference, this suggests that the etiologies of bilateral and unilateral cataract are different.

Adolescent↗
PubMed2004

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.

Adolescent↗
PubMed2004

A nationwide Danish study of 1027 cases of congenital/infantile cataracts: etiological and clinical classifications.

OBJECTIVE: To study the distribution of congenital/infantile cataract in the entire population of Denmark according to etiological and clinical classifications. DESIGN: Population-based cohort study with retrospective chart review. PARTICIPANTS: All children (0 to 17 years old) who were born between 1959 and 2001 and registered with congenital/infantile cataract in Denmark during the period 1977 to 2001. Cases were ascertained from the mandatory Danish National Register of Patients, and all medical records were reviewed. METHODS: Etiological and clinical classifications of the cataract cases were based on information from the medical records. MAIN OUTCOME MEASURES: Classification of congenital/infantile cataract according to presumed etiology; gender; clinical appearance, including laterality and morphology; and the time trends according to etiology and laterality. RESULTS: A total of 1027 children with congenital/infantile cataract, 529 boys and 498 girls, were included, of whom 64% were bilateral. Males predominated with bilateral cataract, whereas females predominated with unilateral cases. Isolated cataract was the most frequent clinical presentation (71% of all cases), followed by an even proportion of cataract associated with additional ocular dysmorphology and cataract associated with systemic anomalies. Almost two thirds of all cases had an unknown etiology (idiopathic). Idiopathic cases showed a higher proportion of unilateral cataract and of additional ocular dysmorphology compared with cases of known etiology. The etiology was unknown in 87% of unilateral cases and in 50% of bilateral cases. The distribution by presumed etiology was stable during the study period, except for cataract caused by maternal infections, which decreased mainly due to the elimination of congenital rubella. CONCLUSIONS: With the exception of the decline of congenital rubella, the proportion of congenital/infantile cataract cases of unknown, genetic, and infectious origins has been stable since the late 1970s. The causes of 87% of unilateral cataracts and 50% of bilateral congenital/infantile cataracts remain unknown, making the prevention of the disease a continuing challenge.

Adolescent↗
PubMed2004

Oculometric characteristics of extreme hypermetropia in two faroese families.

PURPOSE: To describe and analyze the oculometric features of small eyes with high hypermetropia in two Faroese families, with emphasis on refractive components. METHODS: Members of the two families (N=40; age, 1 to 77 years), including 15 cases of extreme hypermetropia (+7.5 to +19.25 D), had an ophthalmic evaluation including refractometry, keratometry, and axial ocular measurements using A-scan ultrasound. Eye-wall thickness was assessed using B-scan. Nonparametric statistics were used, mainly the Mann-Whitney U test. RESULTS: In the two families, there were six and nine probands, respectively, with hypermetropia more than +7 D and short eyes as defined by axial eye lengths <21 mm. The median corrected visual acuity was 0.4 (range, 0.2 to 0.9). Gross fundus abnormalities were not observed. All 15 had a short posterior segment with a thick eye wall and a relatively thick lens. Furthermore, steep and rather small corneas were present. In one of the families, 70% of the affected had a corneal curvature radius of < or =7.0 mm. Five probands from family 2 were labeled as possibly affected because of hypermetropia and borderline axial length findings (21 to 22 mm). The remaining 20 subjects had visual acuity and oculometric findings within physiologic limits. CONCLUSIONS: The axial measurement features in our series of highly hypermetropic eyes mainly presented as an extension downward from the hypermetropic bottom line of the normal distribution. The axial shortness of the eyes was primarily the result of a short posterior eye segment ("posterior microphthalmos"). A steep cornea was a feature in most small eyes in our series, particularly in one family branch.

Adolescent↗
PubMed2004

Incidence and cumulative risk of childhood cataract in a cohort of 2.6 million Danish children.

PURPOSE: To determine the incidence and cumulative risk of childhood cataract in Denmark during 1980 to 2000. METHODS: A cohort of 2,616,439 Danish children born between 1962 and 2000 was followed from 1980 or from the day of birth, whichever occurred later, until their 18th birthday, death, emigration, or diagnosis of cataract, whichever occurred first. Cases were ascertained from the Danish National Register of Patients (NRP) and validated by reviewing the medical records. They were divided into four groups: congenital/infantile (CI) cataract, traumatic cataract, complicated cataract, and "other" types of cataract. RESULTS: After diagnostic validation, 1311 children with cataract (59% with CI cataract) were included in the study. During 1995 to 2000 the overall cumulative risk of childhood cataract was 108.4 per 100,000 children. There was no significant difference in incidence between girls and boys or over time (1980 to 2000) for CI, complicated, and "other" types of cataract. In contrast, the incidence of traumatic cataract was significantly higher among boys. It remained increased during the entire study period despite a 23% decrease per 5 years among boys. Sixty-six percent of the children diagnosed with CI cataract below 2 years of age underwent surgery within 1 year. CONCLUSIONS: The stable incidence during a 20-year period of CI cataract and complicated cataract indicates that risk factors for these conditions have remained unchanged, whereas the marked drop of traumatic cataract among boys most likely reflects changed behavior and an increased focus on preventive measures.

Adolescent↗
PubMed2004

Variant phenotypes of incomplete achromatopsia in two cousins with GNAT2 gene mutations.

PURPOSE: The present study was designed to elucidate the molecular genetic basis of a congenital stationary cone dysfunction characterized by congenital nystagmus, moderate visual impairment, and markedly disparate color vision deficiencies between two affected cousins. METHODS: Ophthalmic examinations with emphasis on color vision and electrophysiology. Molecular genetic analysis of the X-linked cone opsin genes, mutation screening of the CNGA3, CNGB3, and GNAT2 genes, and heterologous splicing experiments. RESULTS: Whereas the proband was found to carry a homozygous frameshift mutation (Tyr95fs) in GNAT2, her cousin was compound heterozygous for the Tyr95fs and a new intronic mutation c.461 + 24G-->A. Heterologous expression in COS7 cells showed that the latter causes a splicing defect that results in early translation termination. Yet, this mutation is leaky, giving rise to small amounts of correctly spliced transcripts and offer an explanation for the diverging clinical findings in the cousins, one best described as incomplete achromatopsia and the other with oligocone trichromacy. CONCLUSIONS: The cases presented broaden the phenotypic spectrum of GNAT2 mutations and underline the increasing importance of molecular genetics in the clinical diagnosis of atypical ophthalmic phenotypes.

Adolescent↗
PubMed2003

ACL reconstruction with hamstring tendon.

The technique of quadrupled semitendinosus autograft for ACL reconstruction using the EndoButton for femoral fixation has been described. Dr. Rosenberg, this article's senior author, has used this for over 10 years with no known instance of fixation failure at the femur or tibia. This technique using QST reconstruction has little morbidity, low reoperation rate, and excellent clinical results.

Anterior Cruciate Ligament↗
PubMed2003

The prevalence and incidence of visual impairment in people of age 20-59 years in industrialized countries: a review.

BACKGROUND: Reviews on the prevalence of blindness and low vision in persons of age 20 to 59 years are lacking. We have therefore carried out a review based on a Medline search. METHODS: The review was confined to epidemiological studies performed in Western Europe, North America and Australia covering the age group 20 to 59 years where there were comparable definitions of blindness and low vision according to the IAPB and WHO classification of blindness and low vision. RESULTS: Three surveys, four register studies and two studies based on multiple sources matched our selection criteria. Blindness and low vision are described separately. Blindness: Only one study, based on multiple sources, covered the whole age group 20 to 59 years. In this study the overall prevalence of blindness was 0.08%. The prevalence of blindness was 0.04% among those 20-39 years old, whereas in the age group 40-59 years it was 0.1% in two surveys and one study on multiple sources. However, the prevalence was higher, 0.5% among whites and 0.7% among colored, in The Baltimore Eye Study. The definition of blindness was similar in all three studies. Low vision: Three studies provided data on the prevalence of low vision in the age group 20-59 years, although the number of cases was very small. In one study the prevalence of a visual acuity < or = 6/24 to 6/48 was 0.07% and in another the prevalence was 0.17% using < 6/18 to 0.5/60. No person with low vision was found in the third study. CONCLUSIONS: The existing epidemiological data on blindness and low vision among adults aged 20 to 59 years are insufficient. Epidemiological studies based on multiple sources are needed for the study of rare conditions such as blindness and low vision.

Adult↗
PubMed2003

Epidemiology of hereditary ocular disorders.

Molecular genetic evidence has contributed significantly to the understanding of the fundamental molecular biology of the eye in health and disease, but it has also exposed the inadequacy of our traditional clinically based classification of hereditary eye disorders by unravelling significant genetic non-allelic heterogeneity in many eye disorders. Furthermore, our understanding of the epidemiology of hereditary ocular disorders has gained considerably by the establishment of mutation spectra in a rapidly growing number of monogenic eye disorders. In this overview, special emphasis has been put on the growing impact of genetic eye diseases in visual impairment, genetic heterogeneity, and the role of founder mutations for the skewed appearance of certain hereditary ocular disorders in some populations.

Eye Diseases↗