Biomedical subjects

W S Oetting

Publications and source records attributed to W S Oetting.

At least 19 recordsLinked to original sources

PubMed2000

Gene expression analysis.

The response of cells to extracellular signals usually requires altered expression of many genes, possibly including several distinct metabolic pathways. In some cases, only a subset of genes involved in such responses are known, which requires techniques to analyze changes in the expression of multiple genes, both known and unknown. Three techniques, two-dimensional gel electrophoresis, differential display, and gene discovery arrays, provide opportunities for measuring changes in gene expression levels, as well as for identifying novel gene products.

Animals↗

PubMed2000

The tyrosinase gene and oculocutaneous albinism type 1 (OCA1): A model for understanding the molecular biology of melanin formation.

Through the last century there has been a steady progression in our understanding of the biology of melanin biosynthesis. Much of this work includes the analysis of coat color mutations of the mouse and albinism in man. Our understanding has been greatly enhanced in the last 10 years, as the molecular pathogenesis of albinism has been better understood. Different mutations of the tyrosinase gene (TYR) , and their association with oculocutaneous albinism type 1 (OCA1) has provided insight into the biology of tyrosinase, including protein trafficking and structure/function analysis. Several questions still remain, including cryptic mutations that affect tyrosinase activity and the minimum amount of pigment required for normal optic development. The next 10 years should prove just as exciting as the last.

Albinism, Oculocutaneous↗

PubMed2000

BRCA1 susceptibility markers and postmenopausal breast cancer: the Iowa Women's Health Study.

Much research on early-onset breast cancer families has been performed and has shown that breast cancer in many of these families is linked to either BRCA1 or BRCA2. Fewer studies have examined the role of genetic predisposition in postmenopausal breast cancer. A nested case-control family study of breast cancer was conducted within the Iowa Women's Health Study, a population-based prospective study of 41,836 postmenopausal women. Probands were 251 incident cases diagnosed between 1988 and 1989. Three-generation pedigrees were developed through mailed questionnaires. From this collection of pedigrees, thirteen were identified for more detailed genetic analysis. Sibling-pair linkage analyses were performed using polymorphic markers in candidate regions in these 13 families with multiple cases of breast and other cancers. Four of the DNA markers are located on chromosome 17, and two of these (D17S579 and THRA1) flank the BRCA1 locus. Significant evidence for linkage to D17S579 was obtained in the total sample, in a model without inclusion of covariates or age at onset (P = 0.005), and in a model adjusted for five measured covariates and for variable age at onset (P = 0.008). Complete sequencing of the BRCA1 gene in these families, including all intron/exon boundaries, failed to reveal any mutations in 24 women with breast cancer from the 13 families. These data suggest that in some families identified by postmenopausal breast cancer cases, breast cancer risk may be mediated by a gene (or genes) in the BRCA1 region, but not BRCA1 itself.

Adult↗

PubMed2000

Evidence for genetic heterogeneity in families with congenital motor nystagmus (CN).

Congenital motor nystagmus (CN) is a relatively common genetic disorder (approximately 1 in 1500) characterized by bilateral involuntary ocular oscillations, with onset occurring within the first six months of life. To date, three loci associated with CN have been mapped to chromosomes 6p12, Xp11.4-p11.3, and Xq26-q27. We analyzed five pedigrees segregating for CN. Mapping studies using markers in these three regions showed that only one pedigree exhibited suggestive linkage with a lod score of 2.08, straight theta=0.0, at chromosome Xp11. This pedigree had both affected male and female members, with two unaffected obligate female carriers. The remaining four pedigrees did not exhibit evidence of linkage for any of the three chromosome locations. Three of the pedigrees, Pedigrees 2, 4, and 5, exhibited several instances of male-to-male transmission, excluding X-linkage, and exhibited a lod score of -3.82, straight theta=0.0, for marker D6S459 located at 6p12, thus excluding the chromosome 6 locus. This provides evidence for at least a fourth locus associated with CN.

Chromosome Mapping↗

PubMed1999

Molecular basis of albinism: mutations and polymorphisms of pigmentation genes associated with albinism.

Albinism, caused by a deficiency of melanin pigment in the skin, hair, and eye (oculocutaneous albinism [OCA]), or primarily in the eye (ocular albinism [OA]), results from mutations in genes involved in the biosynthesis of melanin pigment. The lack of melanin pigment in the developing eye leads to fovea hypoplasia and abnormal routing of the optic nerves. These changes are responsible for the nystagmus, strabismus, and reduced visual acuity common to all types of albinism. Mutations in six genes have been reported to be responsible for different types of oculocutaneous and ocular albinism, including the tyrosinase gene (TYR) and OCA1 (MIM# 203100), the OCA2 gene and OCA2 (MIM# 203200), the tyrosinase-related protein-1 gene (TYRP1) and OCA3 (MIM# 203290), the HPS gene and Hermansky-Pudlak syndrome (MIM# 203300), the CHS gene (CHS1), and Chediak-Higashi syndrome (MIM# 214500), and the X-linked ocular albinism gene and OA1 (MIM#300500). The function of only two of the gene products is known tyrosinase and tyrosinase-related protein-1 both of which are enzymes in the melanin biosynthetic pathway. Continued mutational analysis coupled with function/structure studies should aid our understanding of the function of the remaining genes and their role in albinism. Mutation and polymorphism data on these genes are available from the International Albinism Center Albinism Database web site (http://www.cbc.umn.edu/tad).

Albinism↗

PubMed1999

Albinism.

Albinism was one of the first genetic diseases to be noted in humans, but until relatively recently, little was known of the molecular mechanisms involved in its pathogenesis. Recent advances have shown us that mutations in at least seven different genes can cause a reduction in melanin pigment biosynthesis, producing the various associated clinical features associated with albinism, including hypopigmentation of the skin, hair, and eyes; optic track misrouting; foveal hypoplasia; and reduced visual acuity. Analysis of mutations in these seven genes has revealed that the phenotypic spectrum associated with albinism is broad, making molecular analysis an important part in the accurate diagnosis of this disease.

Albinism↗

PubMed1999

Microphthalmia-associated transcription factor (MITF) locus lacks linkage to human vitiligo or osteopetrosis: an evaluation.

The microphthalmia-associated transcription factor (MITF) locus has been mapped to human chromosome 3p12-p14.1, and encodes a basic helix-loop-helix zipper (bHLH-ZIP) protein homologous to a number of transcription factors. Numerous mutations at the mouse microphthalmia (mi) locus have been described, and all have reduced or absent pigmentation of the eyes, ears, and/or pelage, with some genotypes exhibiting small or absent eyes and osteopetrosis. The mivit/vit mutation at the mouse mi locus produces a postnatal depigmentation that resembles human vitiligo. The mice homozygous for this mi allele show a progressive loss of cutaneous, hair and ocular pigmentation with age. Vitiligo, an acquired depigmentary disorder, is characterized by patchy depigmentation of skin that generally begins around puberty and tends to become more progressive over time. There is suggestive evidence that human vitiligo may be inherited; however, the mode of inheritance is still debated and the pathogenesis is not clearly delineated. The human disorder osteopetrosis is characterized by a generalized net accumulation of skeletal mass and results from reduced osteoclast function in the bone. This is an inherited disorder and has been associated with mi in a mutant mouse. Therefore, the possible involvement of the MITF locus in the pathogenesis of either familial vitiligo or osteopetrosis was investigated. Linkage analysis was performed using microsatellite polymorphic markers D3S2465, D3S1261, and D3S1766 on genomic DNA from 26 families with vitiligo/osteopetrosis. D3S1261 is physically located at or near the MITF locus, while D3S2465 and D3S1766 are flanking the locus at about 17.5 cM genetic distance each side. Evidence from LOD score analysis surprisingly indicated that none of the families with vitiligo or osteopetrosis are linked to these short tandem repeat polymorphisms (STRPs). Thus, the human homolog (MITF) of the mouse mi gene, a good candidate gene at the phenotypic level, may not be involved in the pathogenesis of familial human vitiligo or osteopetrosis.

Adolescent↗

PubMed1999

Fifty-year follow-up of cancer incidence in a historical cohort of Minnesota breast cancer families.

A family history of breast cancer is well established as a risk factor for the disease. Because family history is a dynamic rather than a static characteristic, longitudinal studies of entire families can be very instructive in quantifying the significance of risk classification. The Minnesota Breast Cancer Family Study is a historical cohort study of relatives of a consecutive series of 426 breast cancer cases (probands) identified between 1944 and 1952. The incidence of cancer and the measurement of risk factors in sisters, daughters, granddaughters, nieces, and marry-ins was determined through telephone interviews and mailed questionnaires. Ninety-eight percent of eligible families were recruited, and 93% of members participated. A total of 9073 at-risk women were studied: 56% were biological relatives of the case probands, whereas the others were related through marriage. Through 1996, 564 breast cancers were identified in nonprobands. Compared to the rate of breast cancer among marry-ins (188 cases), sisters and daughters of the probands were at a 1.9-fold greater age-adjusted risk (128 cases; 95% confidence interval, 1.4-2.4); granddaughters and nieces were at a 1.5-fold greater risk (248 cases, 95% confidence interval, 1.2-1.8). The breast cancer risk since 1952 was not distributed equally across families: although all biological relatives had a family history of breast cancer, 166 families (39%) experienced no additional cases. Most of the cases occurred among a subset of families: 21 families had 5 breast or ovarian cancers, 8 had 6, 2 had 7, and 4 had > or =8. There was no evidence of significantly increased risk for cancer at other sites, including the ovaries, cervix, uterus, colon, pancreas, stomach, or lymphatic tissue, although there was some evidence that stomach cancer in previous generations may help define the susceptible subset. These families contain four to five generations of validated occurrences of cancer, thus minimizing the uncertainty of genetic risk inherent in a disease with a late and variable age at onset. The patterns of breast cancer in these multigeneration families is consistent with the influence of autosomal dominant susceptibility in a subset, low penetrance genes in another, and purely environmental influences in the remainder.

Adolescent↗

PubMed1998

Mutations of the human tyrosinase gene associated with tyrosinase related oculocutaneous albinism (OCA1). Mutations in brief no. 204. Online.

Mutations in the human tyrosinase gene produce tyrosinase-related oculocutaneous albinism (OCA1, MIM #203100). Tyrosinase is a copper containing enzyme and is responsible for catalyzing the rate limiting step in melanin biosynthesis, the hydroxylation of tyrosine to dopaquinone. We report 13 new mutations in the tyrosinase gene associated with OCA1A (without pigment) and OCA1B (with pigment) including 9 missense mutations (H19Q, R521, R77C, G97R, C289R, L312V, P313R, F340L and H404P), two nonsense mutations (W80X and R116X) and two frameshift mutations (53delG and 223 delG). Our previous work has defined clusters of missense mutations that appear to represent functional domains of the enzyme, and three of the missense mutations fall into these clusters including two (F340L and H404P) that flank the copper B bindng site and the missense mutation R52I that is located in the amino terminal end cluster of the protein. The G97R missense mutation is the first identified within the epidermal growth factor (EGF)-like sequence and the H19Q missense mutation alters the cleavage site of the signal peptide sequence. Mutational analysis can provide a definitive diagnosis of the type of OCA as well as help structure/function analysis.

Albinism, Oculocutaneous↗

PubMed1998

Mutations of the human P gene associated with Type II oculocutaneous albinism (OCA2). Mutations in brief no. 205. Online.

Mutations in the human P gene lead to oculocutaneous albinism type 2 (OCA2, MIM #203200), the most common type of albinism in humans. The P gene encodes a 110 kDa protein that is associated with melonosomal membranes and contains 12 potential membrane spanning domains. The specific function of the P protein is currently unknown. We report 7 new mutations in the P gene associated with OCA2. This includes 6 missense mutations (S86R, C112F, A368V, T592I, A724P and A787V) and one frameshift mutation (1047del7). We also report 8 polymorphisms including one amino acid substitution, D/A257. We and others have found many polymorphisms of the P gene in the coding region, several of which result in amino acid substitutions, making molecular diagnosis problematic. In contrast to this is the tyrosinase gene associated with OCA1, with a limited number of polymorphic variations in the coding region. There is also no apparent clustering of P gene missense mutations in contrast to the clustering observed by the tyrosinase gene missense mutations that define functional domains of the protein. Further mutational analysis is needed to help define the critical functional domains of the P protein and to allow a definitive diagnosis of OCA2.

Albinism, Oculocutaneous↗

PubMed1998

Multiplexed short tandem repeat polymorphisms of the Weber 8A set of markers using tailed primers and infrared fluorescence detection.

Short tandem repeat polymorphism (STRP) markers have become important reagents for mapping genetic diseases. These markers are available as screening sets, which are located in all chromosomes at discrete intervals, allowing the entire genome to be analyzed. Mapping studies that include many individuals in the analysis necessitate the production of large numbers of genotypes. In an effort to increase the efficiency and lower the cost of using these STRP screening sets, we have divided the amplification primers of the Weber 8A screening set into groups that can be amplified in single polymerase chain reaction (PCR) amplification reactions, resulting in a reduction of both time and cost. Fluorescently-labeled amplification products were produced using a three primer reaction. The forward STRP amplification primer for each marker contained a 19 bp sequence at the 5' end. A fluorescently-labeled primer, with a sequence identical to the 19 bp tail, was added to the amplification reaction as the sole source of fluorescent label. The STRP banding pattern is detected using an automated fluorescent DNA sequencer. Use of this multiplexed genomic screening set should greatly enhance the mapping of human disease loci.

DNA Primers↗

PubMed1998

Identification of a novel transcript produced by the gene responsible for the Hermansky-Pudlak syndrome in Puerto Rico.

Hermansky-Pudlak Syndrome (HPS) is a rare, autosomal recessive disorder that is characterized by oculocutaneous albinism, a predisposition to mild bleeding caused by storage-pool deficient platelets, and a ceroid storage disorder. A gene responsible for HPS in Puerto Rico maps to chromosome 10q2 and isolation of the gene has been reported. We have now identified a variant HPS cDNA that contains the same 5' sequence as the published HPS gene and a unique 3' sequence. Analysis of genomic DNA suggests that the two cDNA are derived from alternative transcripts of a single gene; two polyadenylated transcripts were found in normal human melanocytes, human bone marrow cells, human melanoma cells, lymphoblastoid cell lines, and megakaryocytic leukemia cells by reverse transcriptase polymerase chain reaction and northern analysis. The splicing exhibited by this gene is identical to the splicing found to produce two alternative transcripts of the Chediak-Higashi Syndrome gene, another pigment disorder exhibiting platelet storage pool deficiency. These studies show that the HPS gene on chromosome 10 is complex and may have more than one biologically active transcript.

Albinism, Oculocutaneous↗

PubMed1998

Evidence that a locus for familial high myopia maps to chromosome 18p.

Myopia, or nearsightedness, is the most common human eye disorder. A genomewide screen was conducted to map the gene(s) associated with high, early-onset, autosomal dominant myopia. Eight families that each included two or more individuals with >=-6.00 diopters (D) myopia, in two or more successive generations, were identified. Myopic individuals had no clinical evidence of connective-tissue abnormalities, and the average age at diagnosis of myopia was 6.8 years. The average spherical component refractive error for the affected individuals was -9.48 D. The families contained 82 individuals; of these, DNA was available for 71 (37 affected). Markers flanking or intragenic to the genes for Stickler syndrome types 1 and 2 (chromosomes 12q13.1-q13.3 and 6p21.3, respectively), Marfan syndrome (chromosome 15q21.1), and juvenile glaucoma (chromosome 1q21-q31) were also analyzed. No evidence of linkage was found for markers for the Stickler syndrome types 1 and 2, the Marfan syndrome, or the juvenile glaucoma loci. After a genomewide search, evidence of significant linkage was found on chromosome 18p. The maximum LOD score was 9.59, with marker D18S481, at a recombination fraction of .0010. Haplotype analysis further refined this myopia locus to a 7.6-cM interval between markers D18S59 and D18S1138 on 18p11.31.

Chromosome Mapping↗

PubMed1998

A second locus for familial high myopia maps to chromosome 12q.

Myopia, or nearsightedness, is the most common eye disorder worldwide. "Pathologic" high myopia, or myopia of <=-6.00 diopters, predisposes individuals to retinal detachment, macular degeneration, cataract, or glaucoma. A locus for autosomal dominant pathologic high myopia has been mapped to 18p11.31. We now report significant linkage of high myopia to a second locus at the 12q21-23 region in a large German/Italian family. The family had no clinical evidence of connective-tissue abnormalities or glaucoma. The average age at diagnosis of myopia was 5.9 years. The average spherical-component refractive error for the affected individuals was -9.47 diopters. Markers flanking or intragenic to the genes for the 18p locus, Stickler syndromes type I and II (12q13.1-q13.3 and 6p21.3), Marfan syndrome (15q21.1), and juvenile glaucoma (chromosome 1q21-q31) showed no linkage to the myopia in this family. The maximum LOD score with two-point linkage analysis in this pedigree was 3.85 at a recombination fraction of .0010, for markers D12S1706 and D12S327. Recombination events identified markers D12S1684 and D12S1605 as flanking markers that define a 30.1-cM interval on chromosome 12q21-23, for the second myopia gene. These results confirm genetic heterogeneity of myopia. The identification of this gene may provide insight into the pathophysiology of myopia and eye development.

Adult↗

PubMed1996

The clinical spectrum of albinism in humans.

Oculocutaneous albinism is characterized by a congenital reduction or absence of melanin pigment in the skin, hair and eyes. The reduction in the hair and skin results in a change in color but no change in the development or function of these tissues, while the absence of melanin pigment in the eye leads to abnormal development and function. Of particular interest are mutations that are associated with a slow accumulation of pigment in the hair and eyes over time, while retaining the ocular defects of albinism. Analysis of these mutations might provide the insight that we need to understand the interaction between the pigment system and the development of the optic system.

Albinism, Oculocutaneous↗

PubMed1996

Diagnosis of oculocutaneous albinism with molecular analysis.

PURPOSE: To use molecular analysis to diagnose oculocutaneous albinism in a patient with an atypical clinical presentation. METHODS: A 34-year-old woman with a history of strabismus and absent cutaneous pigment underwent comprehensive ophthalmic examination, visual-evoked potentials to detect altered optic decussation, and molecular analysis. RESULTS: Examination showed fine nystagmus, iris transillumination, foveal hypoplasia, and corrected visual acuity of 20/25 in each eye. Misrouting of the retinostriate fibers was demonstrated with visual-evoked potentials. Mutations in the tyrosinase gene established the diagnosis of oculocutaneous albinism 1 even though the patient had atypical clinical features. CONCLUSIONS: Molecular analysis can establish the diagnosis of oculocutaneous albinism 1 in the patient with atypical ocular features.

Adult↗

PubMed1996

Mutation in and lack of expression of tyrosinase-related protein-1 (TRP-1) in melanocytes from an individual with brown oculocutaneous albinism: a new subtype of albinism classified as "OCA3".

Most types of human oculocutaneous albinism (OCA) result from mutations in the gene for tyrosinase (OCA1) or the P protein (OCA2), although other types of OCA have been described but have not been mapped to specific loci. Melanocytes were cultured from an African-American with OCA, who exhibited the phenotype of Brown OCA, and his normal fraternal twin. Melanocytes cultured from the patient with OCA and the normal twin appeared brown versus black, respectively. Melanocytes from both the patient with OCA and the normal twin demonstrated equal amounts of NP-40-soluble melanin; however, melanocytes from the patient with OCA contained only 7% of the amount of insoluble melanin found from the normal twin. Tyrosinase- related protein-1 (TRP-1) was not detected in the OCA melanocytes by use of various anti-TRP-1 probes. Furthermore, transcripts for TRP-1 were absent in cultured OCA melanocytes. The affected twin was homozygous for a single-bp deletion in exon 6, removing an A in codon 368 and leading to a premature stop at codon 384. Tyrosine hydroxylase activity of the OCA melanocytes was comparable to controls when assayed in cell lysates but was only 30% of controls when assayed in intact cells. We conclude that this mutation of the human TRP-1 gene affects its interaction with tyrosinase, resulting in dysregulation of tyrosinase activity, promotes the synthesis of brown versus black melanin, and is responsible for a third genetic type of OCA in humans, which we classify as "OCA3."

Albinism, Oculocutaneous↗

PubMed1995

Linkage analysis with multiplexed short tandem repeat polymorphisms using infrared fluorescence and M13 tailed primers.

The use of short tandem repeat polymorphisms (STRPs) as marker loci for linkage analysis is becoming increasingly important due to their large numbers in the human genome and their high degree of polymorphism. Fluorescence-based detection of the STRP pattern with an automated DNA sequencer has improved the efficiency of this technique by eliminating the need for radioactivity and producing a digitized autoradiogram-like image that can be used for computer analysis. In an effort to simplify the procedure and to reduce the cost of fluorescence STRP analysis, we have developed a technique known as multiplexing STRPs with tailed primers (MSTP) using primers that have a 19-bp extension, identical to the sequence of an M13 sequencing primer, on the 5' end of the forward primer in conjunction with multiplexing several primer pairs in a single polymerase chain reaction (PCR) amplification. The banding pattern is detected with the addition of the M13 primer-dye conjugate as the sole primer conjugated to the fluorescent dye, eliminating the need for direct conjugation of the infrared fluorescent dye to the STRP primers. The use of MSTP for linkage analysis greatly reduces the number of PCR reactions. Up to five primer pairs can be multiplexed together in the same reaction. At present, a set of 148 STRP markers spaced at an average genetic distance of 28 cM throughout the autosomal genome can be analyzed in 37 sets of multiplexed amplification reactions. We have automated the analysis of these patterns for linkage using software that both detects the STRP banding pattern and determines their sizes. This information can then be exported in a user-defined format from a database manager for linkage analysis.

Chromosome Mapping↗