ER-to-Golgi transport and SEC23-dependent COPII vesicles regulate T cell alloimmunity.

T cell-mediated responses are dependent on their secretion of key effector molecules. However, the critical molecular determinants of the secretion of these proteins are largely undefined. Here, we demonstrate that T cell activation increases trafficking via the ER-to-Golgi pathway. To study the functional role of this pathway, we generated mice with a T cell-specific deletion in SEC23B, a core subunit of coat protein complex II (COPII). We found that SEC23B critically regulated the T cell secretome following activation. SEC23B-deficient T cells exhibited a proliferative defect and reduced effector functions in vitro, as well as in experimental models of allogeneic and xenogeneic hematopoietic cell transplantation in vivo. However, T cells derived from 3 patients with congenital dyserythropoietic anemia II (CDAII), which results from Sec23b mutation, did not exhibit a similar phenotype. Mechanistic studies demonstrated that unlike murine KO T cells, T cells from patients with CDAII harbor increased levels of the closely related paralog, SEC23A. In vivo rescue of murine KO by expression of Sec23a from the Sec23b genomic locus restored T cell functions. Together, our data demonstrate a critical role for the COPII pathway, with evidence for functional overlap in vivo between SEC23 paralogs in the regulation of T cell immunity in both mice and humans.

The R402Q tyrosinase variant does not cause autosomal recessive ocular albinism.

Mutations in the gene for tyrosinase, the key enzyme in melanin synthesis, are responsible for oculocutaneous albinism type 1, and more than 100 mutations of this gene have been identified. The c.1205G > A variant of the tyrosinase gene (rs1126809) predicts p.R402Q and expression studies show thermolabile enzyme activity for the variant protein. The Q402 allele has been associated with autosomal recessive ocular albinism when it is in trans with a tyrosinase gene mutation associated with oculocutaneous albinism type 1. We have identified 12 families with oculocutaneous albinism type 1 that exhibit segregation of the c.1205G > A variant with a known pathologic mutation on the homologous chromosome, and demonstrate no genetic association between autosomal recessive oculocutaneous albinism and the Q402 variant. We conclude that the codon 402 variant of the tyrosinase gene is not associated with albinism.

Bronchoalveolar lavage cell gene expression in acute lung rejection: development of a diagnostic classifier.

BACKGROUND: Acute lung rejection is a risk factor for chronic rejection, which jeopardizes long-term recipient survival. Presently, acute rejection is diagnosed with the use of transbronchial lung biopsies, which are invasive, expensive, and subject to sampling error. We seek to improve acute rejection diagnostics by identifying genes whose expression in bronchoalveolar lavage (BAL) cells best classifies acute rejection versus no rejection. METHODS: BAL samples were analyzed from 32 subjects whose concurrent histology showed acute rejection (n=14) or no rejection (n=18). Gene expression was measured with Affymetrix microarrays. Quantitative real-time polymerase chain reaction confirmed the microarray results for selected genes. The nearest shrunken centroid method with 10-fold cross validation defined the classification model. A total of 250 iterations of the algorithm were performed to determine the misclassification error rate and the most influential genes in determining classifiers. RESULTS: The estimated overall misclassification rate was <20%. Seven transcripts were present in every classifier, and 52 transcripts were present in >70% of classifiers; these transcripts are related to T-cell function, cytotoxic CD8 activity, and granulocyte degranulation. Eleven of the 52 genes were analyzed with quantitative real-time polymerase chain reaction; all were found to significantly different between the groups, with 10 of 11 increased in acute rejection samples. The proportions of lymphocytes and neutrophils in BAL samples increased in acute rejection but did not outperform the gene-based classifier. CONCLUSIONS: There is a prominent acute rejection-associated signature in BAL cells characterized by increased T-cell, CD8 cytotoxic cell, and neutrophil gene expression. These findings lay the foundation for development of rapid PCR-based assays of gene expression for clinical acute rejection diagnosis.

The prevalence of attention-deficit/hyperactivity disorder among persons with albinism.

Attention-deficit/hyperactivity disorder (ADHD) is a common diagnosis in children and adults. Human albinism is an uncommon genetic condition associated with visual impairment that may affect behavior. To determine if there is a relationship between albinism and ADHD, the prevalence of ADHD was examined among 78 children (age range, 4-18 years) and among 44 adults (age range, 19-79 years) with ocular or oculocutaneous albinism. ADHD was diagnosed in the pediatric population using a combination of Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria, Conners' Parent Rating Scale, and physician observation. Adults were diagnosed using the Utah criteria for ADHD as confirmed by physician history and interview. Seventeen children (22.7% [17 of 75]) (3 children with existing diagnoses of pervasive developmental disorder were identified but were not included in the data analysis) and 3 adults (6.8%) met the criteria for ADHD. The combined hyperactivity and impulsivity subtype of ADHD was most common, accounting for 50% of the diagnoses. Binocular best-corrected visual acuity and genetic type of albinism were not found to correlate with a diagnosis of ADHD. The prevalence of ADHD among children and adults with albinism is more frequent than that reported among the general population and is not related to binocular best-corrected visual acuity.

Spectrum of foveal development in albinism detected with optical coherence tomography.

BACKGROUND: Optical coherence tomography (OCT) has shown the absence of a foveal depression in an individual with oculocutaneous albinism, type 1 (OCA1) and best-corrected visual acuity (BCVA) of 20/400. However, the presence of an annular light reflex in the macula has been noted with indirect ophthalmoscopy in other patients with albinism who have better vision. We studied macular architecture in albinism with OCT when binocular BCVA was > or = 20/60 and compared this to detection of foveal development with binocular indirect ophthalmoscopy. METHODS: Eleven patients with albinism and BCVA > or = 20/60 were recruited for OCT. Average central macular thickness was recorded. Presence of an oval annular reflex was determined with binocular indirect ophthalmoscopy. RESULTS: Mean binocular BCVA was 20/39 (range: 20/20 to 20/50). Twelve eyes had a rudimentary annular reflex detected with ophthalmoscopy. OCT was reliable in 20 of 22 eyes. A foveal depression was identified with OCT in four eyes. Mean macular thickness for these four eyes was 233 microm (+/- 22.5 microm). We found a weak inverse correlation between BCVA (logMAR) and thickness (r = -0.21). CONCLUSIONS: OCT shows the spectrum of foveal development in albinism, from complete absence of development to a central depression corresponding to a rudimentary annular reflex detected with ophthalmoscopy. The reduced rate of detection of foveal development with OCT compared with ophthalmoscopy is likely related to poor fixation in patients with nystagmus.

Correlation of grating acuity with letter recognition acuity in children with albinism.

PURPOSE: This study was undertaken to determine whether grating acuity in early childhood can be used as a predictor of letter recognition acuity in patients with albinism. METHODS: In this retrospective study, we compared the binocular grating acuities of children with albinism (30 at age 1, 29 at age 2, and 19 at age 3) to their letter recognition acuity at age 4-6 years. RESULTS: Mean binocular grating acuity was 2.0, 1.9, and 1.5 octaves below age matched norms at ages 1, 2, and 3 years, respectively (P<0.001 at all ages). Mean grating acuity at ages 1, 2, and 3 correlated moderately (r=0.458, 0.502, and 0.471, respectively; all with P<0.05) with mean binocular letter recognition acuity of the same children at ages 4-6. A subgroup analysis of 9 patients followed longitudinally showed strong correlation of binocular grating acuity at ages 1 and 2 with letter acuity (r=0.745, P=0.021; r=0.930, P<0.001, respectively) and moderate correlation at age 3 (r=0.685, P=0.042). In the larger group and the longitudinal subgroup, mean binocular grating acuity at ages 1 and 2 was worse than mean binocular letter recognition acuity at age 4-6 (paired-samples t-test, P<0.001). Mean binocular grating acuity at age 3 in both groups was not significantly different than mean binocular letter recognition acuity at age 4-6 (paired-samples t-test, P=0.790, 0.215, respectively). CONCLUSION: Parents should be informed that vision measured as grating acuity at age 3 provides an estimate of future letter recognition acuity in children with albinism.

P gene mutations associated with oculocutaneous albinism type II (OCA2).

Oculocutaneous albinism type II (OCA2) is the most common form of albinism in humans. OCA2 has been previously associated with mutations of the P gene, the human homologue to the murine pink-eyed dilution gene. The P gene encodes a 110 kDa protein containing 12 potential membrane spanning domains and is associated with melanosomal membranes. The specific function of the P protein is currently unknown but is thought to be involved in tyrosinase processing and transport. We report nine novel mutations in the P gene associated with OCA2. These include two missense mutations, c.1938A>C (p.Ile646Val) and c.1556T>C (p.Val519Ala); one nonsense mutation c.612G>A (p.Trp204X); five frameshift mutations: c.2372_2373delTC, c.1555delG, c.1938_1939insC, c.2050delT, and c.1045_1046delAT; and a splice site mutation c.1951+1G>A. We also report 12 novel polymorphisms including one amino acid substitution, c.2365_2366GC>CA (p.Ala789Glu). At present, there is no functional assay to determine if a mutation is truly pathogenic. The presence of numerous polymorphisms of the P gene in the coding region, several of which result in amino acid substitutions, makes molecular diagnosis problematic. To ensure accurate molecular diagnosis, further mutational analysis will be necessary to produce a comprehensive list of mutations associated with OCA2. This information will also help define the critical functional domains of the P protein. Mutations associated with OCA2 can be found in the Albinism Database (http://albinismdb.med.umn.edu).

Posterior staphyloma in oculocutaneous albinism: another possible cause of reduced visual acuity.

Posterior staphyloma is typically associated with myopic degeneration and has not been recognized as a cause of reduced visual acuity in albinism. We report 3 cases of posterior staphyloma, each with oculocutaneous albinism (OCA) defined by phenotype and genotype. Two cases are biological sisters with OCA type 2; one was myopic and the other was hyperopic. The third case involves a man with OCA associated with Hermansky-Pudlak syndrome (HPS-5). Staphyloma may be another cause of reduced visual acuity in albinism, particularly with increasing age. It may occur in association with myopia or hyperopia.

New locus for autosomal dominant high myopia maps to the long arm of chromosome 17.

PURPOSE: To map the gene(s) associated with autosomal dominant (AD) high-grade myopia. METHODS: A multigeneration English/Canadian family with AD severe myopia was ascertained. Myopes were healthy, with no clinical evidence of syndromic disease, anterior segment abnormalities, or glaucoma. The family contained 22 participating members (12 affected). The average age of diagnosis of myopia was 8.9 years (range, birth to 11 years). The average refractive error for affected adults was -13.925 D (range, -5.50 to -50.00). Microsatellite markers for genotyping were used to assess linkage to several candidate loci, including three previously identified AD high-myopia loci on 18p11.31, 12q22-q23, and 7q36. Syndromic myopia linkage was excluded by using intragenic or flanking markers for Stickler syndrome types 1, 2, and 2B; Marfan syndrome; Ehlers-Danlos syndrome type 4; and juvenile glaucoma. A full genome screening was performed, with 327 microsatellite markers spaced by 5 to 10 cM. Two-point linkage was analyzed using the FASTLINK program run at 90% penetrance and a myopia gene frequency of 0.0133. RESULTS: Linkage to all candidate loci was excluded. The genome screening yielded a maximum two-point lod score of 3.17 at theta = 0 with microsatellite marker D17S1604. Fine mapping and haplotype analysis defined the critical interval of 7.71 cM at 17q21-22. CONCLUSIONS: A novel putative disease locus for AD high-grade myopia has been identified and provides additional support for genetic heterogeneity for this disorder.

Identification of genes expressed in a human scleral cDNA library.

PURPOSE: Clones established from a human scleral cDNA library were systematically sequenced. Public database sequence comparisons were performed to generate a profile of genes expressed in the human sclera and identify candidate genes for inherited diseases with scleral involvement. METHODS: A directionally cloned pCMV-PCR cDNA library was constructed from RNA isolated from scleras of human donor eyes with known plano refractive history. Plasmid DNA was extracted from randomly selected cDNA clones, and the insert sequences were determined by 5' end single-pass sequencing. Expressed sequence tags (ESTs) were generated and analyzed with the GenBank BLASTN program to identify sequence homologies to known genes. RESULTS: A total of 609 ESTs underwent BLAST analysis. Of these, 341 (56%) matched 228 known human genes and 4 non-human genes, 252 matched uncharacterized ESTs, and 16 showed no significant homology to human or non-human known sequences. The most redundant connective tissue-related genes were alphaA-crystalline, Xalpha-1 collagen, and beta-5 integrin. Other extracellular matrix gene matches were biglycan, syndecan, decorin, fibromodulin, proline arginine-rich end leucine-rich repeat protein, transgelin, TIMP-1, and fibulin 1. Human scleral expression of all but decorin and biglycan has not previously been reported. CONCLUSIONS: This effort provides the first partial list of genes expressed in human sclera. Identification of genes expressed in the sclera contributes to our understanding of scleral biology, and potentially provides positional candidate genes for scleral disorders such as high myopia.

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.

Grating acuity in albinism in the first three years of life.

PURPOSE: To compare grating acuity of children 1 to 3 years old with albinism with that of age-matched normal children, and to determine whether ocular pigment and macular structure are predictive of grating visual acuity. METHODS: In this retrospective cross-sectional review of 64 children with albinism, binocular grating acuity was measured with Teller acuity cards at 1, 2, or 3 years of age. Iris transillumination and macular transparency were graded according to published scales. The presence or absence of macular melanin pigment and a rudimentary foveal reflex were assessed with direct and indirect ophthalmoscopy, respectively. RESULTS: Mean grating acuities of the children with albinism at ages 1 (2.48 cycles (cy)/degrees), 2 (3.62 cy/degrees), and 3 (5.87 cy/degrees) were 2.3, 2.1, and 1.7 octaves lower than published norms (all with P <.001). The studied variables did not correlate with visual acuity except for macular transparency at age 2 (r = 0.40; P =.030). CONCLUSIONS: Grating acuity can be used to assess the reduction in visual function in albinism in the first 3 years of life. However, grading of iris transillumination and macular transparency and recognition of an annular reflex or macular melanin do not consistently correlate with the development of vision measured by grating acuity.

Efficacy of spectacles in persons with albinism.

INTRODUCTION: Patients with albinism have varying degrees of reduced vision, strabismus, iris transillumination, nystagmus, fundus hypopigmentation, and foveal hypoplasia. High refractive errors are common, but reduced vision persists due to nonrefractive factors, causing reluctance by some clinicians to prescribe spectacles. We sought to evaluate the effect of spectacle correction of refractive error on clinical findings and recorded compliance with refractive corrections, as little detailed data exist. METHODS: We prospectively examined 35 consecutive patients with albinism for whom glasses had been prescribed to determine if objective improvement in recognition visual acuity (VA), strabismus, anomalous head posture (AHP), fusion, or stereoacuity occurred with refractive correction. Parents or patients reported compliance with glasses wear (excellent: >75% of awake hours; good: 50-75% of awake hours; fair: 26-50% of awake hours; poor: <25%). RESULTS: Median age was 9.5 years (range: 3 to 30). Median refractive correction was 1.875 D spherical equivalent (range: -9.75 to +8.88 D). Glasses wear was initiated at a median age of 14 months (range: 3 months to 14 years). Mean binocular VA at distance was 20/80.9 corrected and 20/107.6 uncorrected ( P < 0.001). Mean VA at near was 20/28.4 corrected and 20/41 uncorrected ( P < 0.001). Mean strabismic deviation was 7.2 PD with glasses and 10.0 PD without glasses at distance ( P = 0.006) and 10.8 PD with glasses and 14 PD without glasses at near ( P = 0.042). Mean AHP at distance was 8.3 degrees with glasses and 7.3 degrees without glasses at distance ( P = 0.327) and 4.7 degrees both with and without glasses at near ( P = 0.308). Twenty-one patients had fusion with or without glasses, two had fusion only with glasses, and one patient had fusion only without glasses. The other patients did not have any detectable degree of fusion. Twenty-seven individuals had no stereoacuity with or without glasses, five had gross stereoacuity of 3000 seconds of arc both with and without glasses, and three had gross stereoacuity only while wearing glasses. Compliance was excellent in 29 patients, fair in four, and poor in two. CONCLUSION: This prospective study showed a significant improvement in corrected VA and alignment in persons with albinism, despite overall subnormal acuity. Some individuals also experienced improvement in binocular alignment and AHP. Compliance with spectacles was generally good. Therefore, refractive correction should be encouraged in persons with albinism as improvement in visual function is likely to occur.

Positive angle kappa in albinism.

BACKGROUND: Albinism is an inherited disorder of deficient melanin production. There is a high prevalence of strabismus in patients with albinism. We investigated the prevalence of a positive angle kappa in patients with albinism and report its effect on assessment of binocular alignment. METHODS: We retrospectively reviewed the charts of 207 consecutive patients with the diagnosis of albinism seen at the University of Minnesota between 1984 and 2002. Angle kappa and alignment using prism and alternate-cover test (PACT) and Krimsky measurements were recorded. RESULTS: In 99.6% of our patients with albinism, angle kappa was noted to be positive. The mean difference between PACT and Krimsky measurements was 17.11 prism diopters in the more exotropic (or less esotropic) direction per Krimsky test. Because of the high prevalence of a positive angle kappa, esodeviations often appeared less and exodeviations appeared greater than when measured using PACT. CONCLUSIONS: Positive angle kappa can be considered another clinical feature of albinism. Consideration should be given to the effect of positive angle kappa on alignment as observed by Krimsky measurement when planning extraocular muscle surgery, particularly when preoperative sensory testing suggests binocular potential.

Change in visual acuity in albinism in the early school years.

PURPOSE: To determine whether binocular best-corrected visual acuity (B-BCVA) improves in the early school years in patients with albinism and whether this is related to type of albinism, ocular pigment, or appearance of the macula. METHODS: Patients with albinism seen between 5.5 and 9 years (Visit A) and 9.5 and 14 years of age (Visit B), with visits separated by at least 2.5 years, were included. Type of albinism, B-BCVA, glasses wear, iris pigment and macular transparency grade, and presence or absence of an annular reflex and melanin in the macula were recorded. RESULTS: Mean B-BCVA was 20/84 at Visit A and 20/61 at Visit B (P < .001). B-BCVA improved in 80%. Improvement in B-BCVA and glasses wear, iris grade, macular grade, macular melanin, and annular reflex were weakly correlated. However, a moderate correlation was found between measured B-BCVA and iris grade at Visit A (r = 0.485, P < .001) and Visit B (r = 0.467, P < .001), and the presence of macular melanin at Visit A (r = 0.436, P < .001) and Visit B (r = 0.482, P < .001). CONCLUSIONS: B-BCVA often improves in albinism in the early school years and this observation should be included in counseling. The etiology is unknown but may be related to change in nystagmus, use of precise null point, developmental maturation, and/or some of the ocular characteristics evaluated in this study.

Novel insights into lung transplant rejection by microarray analysis.

Gene expression microarrays can estimate the prevalence of mRNA for thousands of genes in a small sample of cells or tissue. Organ transplant researchers are increasingly using microarrays to identify specific patterns of gene expression that predict and characterize acute and chronic rejection, and to improve our understanding of the mechanisms underlying organ allograft dysfunction. We used microarrays to assess gene expression in bronchoalveolar lavage cell samples from lung transplant recipients with and without acute rejection on simultaneous lung biopsies. These studies showed increased expression during acute rejection of genes involved in inflammation, apoptosis, and T-cell activation and proliferation. We also studied gene expression during the evolution of airway obliteration in a murine heterotopic tracheal transplant model of chronic rejection. These studies demonstrated specific patterns of gene expression at defined time points after transplantation in allografts, whereas gene expression in isografts reverted back to that of native tracheas within 2 wk after transplantation. These studies demonstrate the potential power of microarrays to identify biomarkers of acute and chronic lung rejection. The application of new genetic, genomic, and proteomic technologies is in its infancy, and the microarray-based studies described here are clearly only the beginning of their application to lung transplantation. The massive amount of data generated per tissue or cell sample has spawned an outpouring of invention in the bioinformatics field, which is developing methodologies to turn data into meaningful and reproducible clinical and mechanistic inferences.

CD14 promoter polymorphisms in atopic families: implications for modulated allergen-specific immunoglobulin E and G1 responses.

BACKGROUND: CD14 promoter DNA sequence polymorphisms for the endotoxin receptor gene have been implicated in modulating allergen-specific immunoglobulin (Ig)E responses in randomly selected individuals with atopy. We sought to determine if a single nucleotide polymorphism in the CD14 promoter region is associated with atopy in atopic families, and to assess its influence on serum levels of CD14 and allergen-specific IgE and IgG1 responses. METHODS: We screened 367 members of 91 Caucasian nuclear families with a history of asthma for pulmonary function by spirometry, including methacholine challenge to detect bronchial hyperreactivity, and atopy by serum total IgE and skin prick test to 14 allergens. The CD14 promoter single nucleotide polymorphism was analyzed in DNA isolated from peripheral blood mononuclear cells to identify C/C, C/T and T/T genotypes. Serum tests were done for soluble CD14 (sCD14) and dust mite-specific antibody (Der p 1-IgG1). RESULTS: Serum sCD14 levels were not associated with clinical phenotypes (asthma, bronchial hyperreactivity or atopy). However, sCD14 levels were inversely related to both allergen-specific IgE and Der p 1-IgG1 production, but only among those with evidence of atopic sensitization. Linear regression analysis, accounting for random family effects, demonstrated a higher production of allergen-specific IgE or Der p 1-IgG1 associated with the T/T genotype and a lower level of specific IgE and IgG1 production associated with sCD14 levels. CONCLUSIONS: An element of the innate immune system (CD14) has profound effects upon modulating the acquired allergen-specific immunoglobulin responses among those with an inherited atopic predisposition.

A genome-wide search for quantitative trait loci contributing to variation in seasonal pollen reactivity.

BACKGROUND: Asthma and atopy represent complex traits for which genetic predisposition has been demonstrated. Pollen sensitivity, whether seasonal or chronic, appears to be a major contributor to the asthmatic phenotype. OBJECTIVE: Regions of the genome contributing to skin test reactivity to 5 seasonal allergens are to be identified in a genome-wide scan. These regions may be distinct from those contributing to risk for asthma and/or atopy. METHODS: In the Collaborative Study on the Genetics of Asthma, 4 sites collected 287 families with 2 or more members with asthma. Reactivity to individual pollens were determined on all family members. A genome scan was performed at 9-centiMorgan intervals, and skin test reactivity to 5 seasonal allergens was the focus of nonparametric genetic linkage analysis. RESULTS: Chromosomal regions that exhibited suggestive linkage (logarithm of the odds >1.18; P < .01) to seasonal pollen reactivity were identified on chromosomes 13q34, 20p12, and 21q21. Evidence of ethnic differences in linkage to seasonal allergens was demonstrated, with support for linkage in African American subjects on chromosomes 8, 10, and 12, in European American subjects on chromosomes 14, 19, 20, and 22, and in Hispanics on chromosome 21. In all families, evidence for linkage of skin test reactivity for Betula, Lolium, and Artemisia was strongest in a region on chromosome 21 that contained the candidate gene, A Disintegrin And Metalloprotease domain 33 (ADAM33). CONCLUSION: These results suggest both substantial genetic overlap and extensive heterogeneity in the genetic basis for the allergic response to seasonal allergens.

A 'touch' of the White platelet syndrome.

Investigations into structural defects in platelets from a large family with the White platelet syndrome (WPS) separated the members into three groups. The first group of 22 members was the subject of our first report (White JG, Key NS, King RA, Vercellotti GM. The white platelet syndrome: A new autosomal dominant platelet disorder. Platelets 2004;15:173-184). A third group of 13 members had no abnormalities of platelet ultrastructure. The second group of 17 members, the focus of the present study, had a 'touch' of the WPS. Platelet counts, mean platelet volumes (MPVs) and platelet responses to aggregating agents were normal in 'touch' patients in contrast to platelets of those with the full WPS in whom these parameters were abnormal. Up to 13% of the full WPS platelets contained large, fully developed Golgi complexes, up to seven in number, extruding innumerable vesicles from the trans-Golgi face and filling the cytoplasm of many platelets. Many Golgi complexes had centrioles associated with them. 'Touch' platelets had one or two Golgi complexes of intermediate size in 3-5% of their platelets. Golgi vesicles were uncommon and centrioles absent. Gray platelets and hypogranular cells were infrequent in patients with a 'touch' of the WPS, whereas up to 44% of the platelets from those with the WPS were gray or hypogranular. Elements of the dense tubular system were prominent in full WPS platelets, together with their formation into areas of cytoplasmic sequestration and autodigestion. These features were absent in 'touch' platelets. As commonly observed in full WPS platelets, mitochondria were larger and more numerous than alpha granules in some 'touch' cells. Both 'touch' and full WPS platelets frequently contained giant and rod-shaped granules. Dense bodies, however, were normal in size and number in 'touch' platelets, and half normal size in full WPS platelets. The separation of ultrastructural abnormalities in the two varieties of the WPS suggests that genetic defects involve more than a single gene and the genes are variable in their penetrance. Genetic studies to determine if this is the case are currently in progress.