Referral networks for pediatric patients with genetic conditions: The perspective of occupational therapists.

Families of children with developmental delays but no diagnosed genetic condition may benefit from connection to genetic systems of care. This work examines the role of occupational therapy as a space for families of pediatric patients to gain access to genetic services. Between September 2021 and February 2022, we interviewed 20 occupational therapists in New England who work primarily with pediatric patients. We transcribed the interviews and used a grounded theory approach to identify and code recurring themes. The data reveal several barriers to linking pediatric patients to genetic systems of care, including lack of insurance coverage, wait times for appointments and test results, hesitant primary care providers, and familial and cultural stigma of disability. We discuss the unique role of occupational therapists as professionals who spend substantial time with patients, often in their everyday environments, to bridge these barriers. We also address challenges associated with occupational therapists facilitating connections to genetics services, including their lack of specialized knowledge of genetics and barriers fully integrating with others on the medical team.

Transport of boron by the tassel-less1 aquaporin is critical for vegetative and reproductive development in maize.

The element boron (B) is an essential plant micronutrient, and B deficiency results in significant crop losses worldwide. The maize (Zea mays) tassel-less1 (tls1) mutant has defects in vegetative and inflorescence development, comparable to the effects of B deficiency. Positional cloning revealed that tls1 encodes a protein in the aquaporin family co-orthologous to known B channel proteins in other species. Transport assays show that the TLS1 protein facilitates the movement of B and water into Xenopus laevis oocytes. B content is reduced in tls1 mutants, and application of B rescues the mutant phenotype, indicating that the TLS1 protein facilitates the movement of B in planta. B is required to cross-link the pectic polysaccharide rhamnogalacturonan II (RG-II) in the cell wall, and the percentage of RG-II dimers is reduced in tls1 inflorescences, indicating that the defects may result from altered cell wall properties. Plants heterozygous for both tls1 and rotten ear (rte), the proposed B efflux transporter, exhibit a dosage-dependent defect in inflorescence development under B-limited conditions, indicating that both TLS1 and RTE function in the same biological processes. Together, our data provide evidence that TLS1 is a B transport facilitator in maize, highlighting the importance of B homeostasis in meristem function.

vanishing tassel2 encodes a grass-specific tryptophan aminotransferase required for vegetative and reproductive development in maize.

Auxin plays a fundamental role in organogenesis in plants. Multiple pathways for auxin biosynthesis have been proposed, but none of the predicted pathways are completely understood. Here, we report the positional cloning and characterization of the vanishing tassel2 (vt2) gene of maize (Zea mays). Phylogenetic analyses indicate that vt2 is a co-ortholog of TRYPTOPHAN AMINOTRANSFERASE OF ARABIDOPSIS1 (TAA1), which converts Trp to indole-3-pyruvic acid in one of four hypothesized Trp-dependent auxin biosynthesis pathways. Unlike single mutations in TAA1, which cause subtle morphological phenotypes in Arabidopsis thaliana, vt2 mutants have dramatic effects on vegetative and reproductive development. vt2 mutants share many similarities with sparse inflorescence1 (spi1) mutants in maize. spi1 is proposed to encode an enzyme in the tryptamine pathway for Trp-dependent auxin biosynthesis, although this biochemical activity has recently been questioned. Surprisingly, spi1 vt2 double mutants had only a slightly more severe phenotype than vt2 single mutants. Furthermore, both spi1 and vt2 single mutants exhibited a reduction in free auxin levels, but the spi1 vt2 double mutants did not have a further reduction compared with vt2 single mutants. Therefore, both spi1 and vt2 function in auxin biosynthesis in maize, possibly in the same pathway rather than independently as previously proposed.

Transitions in caregiving: evaluating a person-centered approach to supporting family caregivers in the community.

Caregivers of older adults provide a wide range of informal supports and services that enable older adults to continue living in the community. This study describes the use of a multicomponent intervention combined with a person-centered approach to assist caregivers of older adults in the community. Four hundred and eighteen caregiver and care recipient dyads participated in this study and their outcomes related to burden, depression, well-being, and care recipient functional status were evaluated. The findings suggest that adult child and spousal caregivers experience burden differently. Programs designed to support caregivers must tailor services to the unique needs of adult child and spousal caregivers.

A maize thiamine auxotroph is defective in shoot meristem maintenance.

Plant shoots undergo organogenesis throughout their life cycle via the perpetuation of stem cell pools called shoot apical meristems (SAMs). SAM maintenance requires the coordinated equilibrium between stem cell division and differentiation and is regulated by integrated networks of gene expression, hormonal signaling, and metabolite sensing. Here, we show that the maize (Zea mays) mutant bladekiller1-R (blk1-R) is defective in leaf blade development and meristem maintenance and exhibits a progressive reduction in SAM size that results in premature shoot abortion. Molecular markers for stem cell maintenance and organ initiation reveal that both of these meristematic functions are progressively compromised in blk1-R mutants, especially in the inflorescence and floral meristems. Positional cloning of blk1-R identified a predicted missense mutation in a highly conserved amino acid encoded by thiamine biosynthesis2 (thi2). Consistent with chromosome dosage studies suggesting that blk1-R is a null mutation, biochemical analyses confirm that the wild-type THI2 enzyme copurifies with a thiazole precursor to thiamine, whereas the mutant enzyme does not. Heterologous expression studies confirm that THI2 is targeted to chloroplasts. All blk1-R mutant phenotypes are rescued by exogenous thiamine supplementation, suggesting that blk1-R is a thiamine auxotroph. These results provide insight into the role of metabolic cofactors, such as thiamine, during the proliferation of stem and initial cell populations.

Food sufficiency and the utilization of free food resources for working-age Americans with disabilities during the COVID-19 pandemic.

BACKGROUND: Working-age people with disabilities are an economically disadvantaged population more likely than those without disabilities to live in food insecure households. OBJECTIVE/HYPOTHESIS: Compare rates of food sufficiency and utilization of free food sources between working-age persons with and without disabilities in the US during the COVID-19 pandemic. METHODS: In September 2020, an online survey was conducted with n = 13,270 working-age individuals with and without disabilities to gather information about food sufficiency prior to COVID-19 (i.e., in March 2020) and within the last seven days as well as receipt of free groceries or meals, use of food programs or pantries, and concerns with using free food sources over the past week. Descriptive and multivariate statistics were used to compare these measures for persons with and without disabilities. RESULTS: Controlling for sociodemographic characteristics, the proportion of working-age persons who were food sufficient decreased from March 2020 to September 2020 for persons with disabilities (59%-53%, a six-percentage point decrease) and for persons without disabilities (77%-73%, a four-percentage point decrease). The rates of change were not significantly different between groups. In September 2020, higher proportions of persons with disabilities (57%) used free food resources in the past week than persons without disabilities (41%). CONCLUSIONS: The low rate of food sufficiency, the high rate of free food resource utilization, and the concerns noted by working-age persons with disabilities in using these sources suggest a need for continuing nutrition assistance policy and program development targeted towards the needs of persons with disabilities.

Time trends in emergency department use among adults with intellectual and developmental disabilities.

BACKGROUND: Emergency Department (ED) visits are common among adults with intellectual and developmental disabilities (IDD). However, little is known about how ED use has varied over time in this population, or how it has been affected by recent Medicaid policy changes. OBJECTIVE: To examine temporal trends in ED use among adult Medicaid members with IDD in eight states that ranged in the extent to which they had implemented state-level Medicaid policy changes that might affect ED use. METHODS: We conducted repeated cross-sectional analyses of 2010-2016 Medicaid claims data. Quarterly analyses included adults ages 18-64 years with IDD (identified by diagnosis codes) who were continuously enrolled in Medicaid for the past 12 months. We assessed change in number of ED visits per 1000 member months from 2010 to 2016 overall and interacted with state level policy changes such as Medicaid expansion. RESULTS: States with no Medicaid expansion experienced an increase in ED visits (linear trend coefficient: 1.13, p < 0.01), while states operating expansion via waiver had a much smaller (non-significant) increase, and states with ACA-governed expansion had a decrease in ED visits (linear trend coefficient: 1.17, p < 0.01). Other policy changes had limited or no association with ED visits. CONCLUSIONS: Medicaid expansion was associated with modest reduction or limited increase in ED visits compared to no expansion. We found no consistent decrease in ED visits in association with other Medicaid policy changes.

Comparative analyses of eighteen rapid antigen tests and RT-PCR for COVID-19 quarantine and surveillance-based isolation.

Background: Rapid antigen (RA) tests are being increasingly employed to detect SARS-CoV-2 infections in quarantine and surveillance. Prior research has focused on RT-PCR testing, a single RA test, or generic diagnostic characteristics of RA tests in assessing testing strategies. Methods: We have conducted a comparative analysis of the post-quarantine transmission, the effective reproduction number during serial testing, and the false-positive rates for 18 RA tests with emergency use authorization from The United States Food and Drug Administration and an RT-PCR test. To quantify the extent of transmission, we developed an analytical mathematical framework informed by COVID-19 infectiousness, test specificity, and temporal diagnostic sensitivity data. Results: We demonstrate that the relative effectiveness of RA tests and RT-PCR testing in reducing post-quarantine transmission depends on the quarantine duration and the turnaround time of testing results. For quarantines of two days or shorter, conducting a RA test on exit from quarantine reduces onward transmission more than a single RT-PCR test (with a 24-h delay) conducted upon exit. Applied to a complementary approach of performing serial testing at a specified frequency paired with isolation of positives, we have shown that RA tests outperform RT-PCR with a 24-h delay. The results from our modeling framework are consistent with quarantine and serial testing data collected from a remote industry setting. Conclusions: These RA test-specific results are an important component of the tool set for policy decision-making, and demonstrate that judicious selection of an appropriate RA test can supply a viable alternative to RT-PCR in efforts to control the spread of disease.

Previous research on SARS-CoV-2 infection has determined optimal timing for testing in quarantine and the utility of different frequencies of testing for infection surveillance using RT-PCR and generalized rapid antigen tests. However, these strategies can depend on the specific rapid antigen test used. By examining 18 rapid antigen tests, we demonstrate that a single rapid antigen test performs better than RT-PCR when quarantines are two days or less in duration. In the context of infection surveillance, the ability of a rapid antigen test to provide results quickly counteracts its lower sensitivity with potentially more false positives. Our findings indicate that rapid antigen tests can be a suitable alternative to RT-PCR for application in quarantine and infection surveillance.

Disability-competence training influences health care providers' conceptualizations of disability: An evaluation study.

BACKGROUND: Often, health care providers' approach to people with disabilities is grounded in a medical model perspective. This view highlights individual deficits and does not foster patient-centeredness. Learning about and adopting a more social model, focused on creating accessible and inclusive approaches and environments, could help providers to reshape their attitudes about disability, dismantling barriers to care. OBJECTIVE: This study used innovative methods to evaluate a recorded, online disability-competence training for health care providers. It was hypothesized that the training would 1) shift providers' conceptualizations of disability away from a medical model view toward a social model view of disability and 2) equip providers with actionable strategies to improve access to care for people with disabilities. METHODS: Quantitative and qualitative evaluation data were analyzed for n = 192 training participants. Measures included participants' pre- and post-training conceptualizations of disability, proposed actions steps to facilitate patient-centered care, and measures of satisfaction and self-assessed knowledge gain. RESULTS: Both hypotheses were supported. After the training, participants' conceptualizations of disability were more reflective of the social model, and participants were better able to articulate specific action steps they could take to promote accessible, responsive care. CONCLUSIONS: This study demonstrates that health care provider training can positively affect providers' knowledge, outlook, and approach to caring for people with disabilities. Its findings can inform broader efforts aimed at systematically changing the way health professionals are educated and trained to provide care in disability-competent ways.

Food sufficiency and the utilization of free food resources for working-age Americans with disabilities during the COVID-19 pandemic.

BACKGROUND: Working-age people with disabilities are an economically disadvantaged population more likely than those without disabilities to live in food insecure households. OBJECTIVE/HYPOTHESIS: Compare rates of food sufficiency and utilization of free food sources between working-age persons with and without disabilities in the US during the COVID-19 pandemic. METHODS: In September 2020, an online survey was conducted with n = 13,277 working-age individuals with and without disabilities to gather information about food sufficiency prior to COVID-19 (i.e., in March 2020) and within the last seven days as well as receipt of free groceries or meals, use of food programs or pantries, and concerns with using free food sources over the past week. Descriptive and multivariate statistics were used to compare these measures for persons with and without disabilities. RESULTS: Controlling for sociodemographic characteristics, the proportion of working-age persons who were food sufficient decreased from March 2020 to September 2020 for persons with disabilities (65%-57%, an eight-percentage point decrease) and for persons without disabilities (78%-73%, a five-percentage point decrease). The rates of change were not significantly different between groups. In September 2020, higher proportions of persons with disabilities (58%) used free food resources in the past week than persons without disabilities (41%). CONCLUSIONS: The low rate of food sufficiency, the high rate of free food resource utilization, and the concerns noted by working-age persons with disabilities in using these sources suggest a need for continuing nutrition assistance policy and program development targeted towards the needs of persons with disabilities.

Ambulatory Care Sensitive Conditions Among All-Payer Claimants With Intellectual and Developmental Disabilities.

Inpatient hospitalizations for ambulatory care sensitive conditions (ACSC) among beneficiaries with and without intellectual and developmental disabilities (IDD) were examined using Medicaid and commercial claims from 2010-2014 in New Hampshire. IDD was defined with International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) codes using algorithms from the Centers for Medicare and Medicaid Services, and inpatient encounters were identified using the Healthcare Effectiveness Data and Information Set. In adjusted analyses, beneficiaries with IDD had more hospitalizations for ACSC than those without IDD in both insurance groups. Differences in patterns of ACSC prevalence, comorbidities, and hospital admissions between the commercially and Medicaid-insured groups show the value of using all-payer claims data, when possible, to understand health needs and health care utilization of insurance beneficiaries with IDD.

Comparison of familial and sporadic chronic lymphocytic leukaemia using high resolution array comparative genomic hybridization.

Approximately 10% of patients with chronic lymphocytic leukaemia (CLL) have a family history of the disease or a related lymphoproliferative disorder, yet the relationship of familial CLL to genomic abnormalities has not been characterized in detail. We therefore studied 75 CLL patients, half familial and half sporadic, using high-resolution array comparative genomic hybridization (CGH), in order to better define the relationship of genomic abnormalities to familial disease and other biological prognostic factors. Our results showed that the most common high-risk deletion in CLL, deletion 11q, was significantly associated with sporadic disease. Comparison of familial to sporadic disease additionally identified a copy number variant region near the centromere on 14q, proximal to IGH@, in which gains were associated both with familial CLL, and with mutated IGHV and homozygous deletion of 13q. Homozygous deletion of 13q was also found to be associated with mutated IGHV and low expression of ZAP-70, and a significantly longer time to first treatment compared to heterozygous deletion or lack of alteration. This study is the first high resolution effort to investigate and report somatic genetic differences between familial and sporadic CLL.

Randomized phase II study of stereotactic body radiotherapy and interleukin-2 versus interleukin-2 in patients with metastatic melanoma.

BACKGROUND: A pilot study of stereotactic body radiation therapy (SBRT) followed by high-dose interleukin-2 (IL-2) showed a higher than anticipated objective response rate (ORR) among patients with metastatic melanoma (MM). We performed a prospective randomized study to determine if the ORR of SBRT + IL-2 was greater than IL-2 monotherapy in patients with advanced melanoma. METHODS: Patients with MM who had adequate physiological reserve for IL-2 and at least one site suitable for SBRT were eligible. There was a 1:1 randomization to SBRT + IL-2 or IL-2 monotherapy. Patients received one or two doses of SBRT (20 Gy per fraction) with the last dose administered 3 days before starting the first cycle of IL-2. IL-2 (600,000 IU per kg via intravenous bolus infusion) was given every 8 hours for a maximum of 14 doses with a second cycle after a 2-week rest. Responding patients received up to six IL-2 cycles. Patients assigned to IL-2 monotherapy who exhibited progression of melanoma after cycle 2 were allowed to crossover and receive SBRT and additional IL-2. Response Evaluation Criteria in Solid Tumors 1.1 criteria were applied to non-irradiated lesions for response assessment. RESULTS: 44 patients were included in the analysis. The ORR in the SBRT + IL-2 group was 54%: 21% complete response (CR), 33% partial response (PR), 21% stable disease (SD) and 25% progressive disease (PD). The ORR in patients receiving IL-2 monotherapy was 35%: 15% CR, 20% PR, 25% SD and 40% PD. Seven patients assigned to IL-2 subsequently received SBRT + IL-2. One CR and two PRs were observed in the crossover group. There was no difference in progression-free or overall survival (OS). At 5 years the OS was 26% in the SBRT + IL-2 group and 25% in the IL-2 monotherapy group. The disease control rate (DCR) was higher in the SBRT + IL-2 group (75% vs 60%, p=0.34). CONCLUSIONS: SBRT + IL-2 induced more objective responses with a higher DCR compared to IL-2 monotherapy in MM. IL-2 monotherapy resulted in a significantly higher ORR than anticipated. Some patients in the crossover group also achieved objective responses. TRIAL REGISTRATION NUMBER: NCT01416831.

A phase 2 study of concurrent fludarabine and rituximab for the treatment of marginal zone lymphomas.

The marginal zone lymphomas (MZLs) are a recently defined group of related diseases that probably arise from a common cell of origin, the marginal zone B cell. Data on therapy for subtypes other than gastric mucosa-associated lymphoid tissue (MALT) lymphoma has been largely limited to retrospective case series. This prospective phase 2 study of fludarabine and rituximab for the treatment of marginal zone lymphomas enrolled 26 patients, 14 with nodal MZL, eight with MALT lymphomas and four with splenic MZL; 81% were receiving initial systemic therapy. Only 58% [95% confidence interval (CI) 37-77%] of patients completed the planned six cycles, due to significant haematological, infectious and allergic toxicity. Four late toxic deaths occurred due to infections [15% (95% CI 4.3-35%)], two related to delayed bone marrow aplasia and two related to myelodysplastic syndrome. Nonetheless, the overall response rate was 85% (95% CI 65-96%), with 54% complete responses. The progression-free survival at 3.1 years of follow-up is 79.5% (95% CI 63-96%). We conclude that, although concurrent fludarabine and rituximab given at this dose and schedule is a highly effective regimen in the treatment of MZLs, the significant haematological and infectious toxicity observed both during and after therapy is prohibitive in this patient population, emphasizing the need to study MZLs as a separate entity.

Prevalence of familial malignancy in a prospectively screened cohort of patients with lymphoproliferative disorders.

Increasing evidence points to a heritable contribution in the development of lymphoma. The goal of this study was to determine the rate of familial lymphoproliferative malignancy among consecutive lymphoma patients presenting to a tertiary care center and to enroll families with multiple affected first-degree relatives on a data and tissue collection study. Beginning in 2004 all new patients presenting to the Dana-Farber Cancer Institute with non-Hodgkin (NHL) or Hodgkin lymphoma (HL) or chronic lymphocytic leukaemia (CLL) were asked to complete a one-page self-administered family history questionnaire. 55.4% of 1948 evaluable patients reported a first-degree relative with a malignancy, with the highest rate among CLL probands. Lymphoid malignancies were particularly common, with 9.4% of all probands reporting a first-degree relative with a related lymphoproliferative disorder (LPD). This frequency was again highest for CLL, at 13.3% of CLL probands, compared to 8.8% of NHL probands and 5.9% of HL probands (P = 0.002). The prevalence of CLL was significantly increased in parents of CLL probands (P < 0.05), and a greater risk of NHL was seen in fathers of NHL probands than in mothers (P = 0.026). We conclude that familial aggregation of LPDs is common among newly diagnosed patients, varies significantly by diagnosis and contributes meaningfully to the population disease burden.

Prevalence and reasons for delaying and foregoing necessary care by the presence and type of disability among working-age adults.

BACKGROUND: While it is commonly accepted that disparities in unmet need for care vary by age, race/ethnicity, income, education, and access to care, literature documenting unmet needs experienced by adults with different types of disabilities is developing. OBJECTIVE: The main objective was to determine whether subgroups of people with disabilities are more likely than people without disabilities to delay/forgo necessary care, in general and among the insured. METHODS: We used pooled Medical Expenditure Panel Survey data (2004-2010) to examine delaying or forgoing medical, dental, and pharmacy care among five disability subgroups (physical, cognitive, visual, hearing, multiple) and the non-disabled population. Logistic regression was conducted to examine delayed/forgone care, controlling for sociodemographic, health, and health care factors. RESULTS: Over 13% of all working-age adults delayed/forwent necessary care; lack of insurance was the strongest predictor of unmet needs. Among the insured, disability subgroups were greater than two times more likely to report delayed/forgone care than adults without disabilities. Insured working-age adults with multiple chronic conditions and those with ADL/IADL assistance needs had higher odds of delayed or forgone care than their peers without these characteristics. Reasons related to affordability were most often listed as leading to unmet needs, regardless of disability. CONCLUSION: Although insurance status most strongly predicted unmet needs for care, many people with insurance delayed/forewent necessary care. Even among the insured, all disability subgroups had significantly greater likelihood of having to delay/forgo care than those without disabilities. Differences also existed between the disability subgroups. Cost was most frequently cited reason for unmet needs.

Asthma and asthma-related health care utilization among people without disabilities and people with physical disabilities.

BACKGROUND: Previous research has shown that people with disabilities have higher rates of some chronic diseases and receive poorer disease-specific care than their counterparts without disabilities. Yet, little is known about the relationship between asthma and disability. OBJECTIVE: This study examines whether differences in the prevalence of asthma, asthma flare, and asthma-related measures of health care quality, utilization and cost exist among people with physical limitations (PL) and without any limitations. METHODS: Data from the 2004-2010 Medical Expenditure Panel Survey were pooled to compare outcomes for working-age adults (18-64) with PL to those with no limitations. RESULTS: People with PL had higher rates of asthma (13.8% vs. 5.9%, p < 0.001) and recent asthma flare (52.6% vs. 39.6%, p < 0.001) than people without limitations. There were no differences in health care quality, utilization or cost between people with PL and people without limitations in multivariate analyses. CONCLUSIONS: Although there are no differences in asthma-related quality or utilization of health care, people with PL have poorer asthma control than people without limitations. Research is needed to determine what factors (e.g., focus on other acute ailments, perceptions that asthma control cannot improve) are related to this outcome. Future research must also examine differences in asthma severity, and its impact on asthma control and health care-related outcomes, among people with and without disabilities.

Developmental disaster1: A novel mutation causing defects during vegetative and inflorescence development in maize (Zea mays, Poaceae).

Axillary meristems, which give rise to branches and flowers, play a critical role in plant architecture and reproduction. To understand how axillary meristems initiate, we have screened for mutants with defects in axillary meristem initiation to uncover the genes controlling this process. These mutants, called the barren class of mutants in maize (Zea mays), have defects in axillary meristem initiation during both vegetative and reproductive development. Here, we identify and characterize a new member of the barren class of mutants named Developmental disaster1 (Dvd1), due to the pleiotropic effects of the mutation. Similar to the barren mutants, Dvd1 mutants have fewer branches, spikelets, florets, and floral organs in the inflorescence due to defects in the initiation of axillary meristems. Furthermore, double mutant analysis with teosinte branched1 shows that dvd1 also functions in axillary meristems during vegetative development. However, unlike the barren mutants, Dvd1 mutants are semidwarf due to the production of shorter internodes, and they produce leaves in the inflorescence due to the outgrowth of bract leaf primordia. The suite of defects seen in Dvd1 mutants, together with the genetic interaction of Dvd1 with barren inflorescence2, suggests that dvd1 is a novel regulator of axillary meristem and internode development.

Younger women's perceptions of coping with breast cancer.

Numerous studies have demonstrated an association between coping strategies and better quality of life after breast cancer. Because younger women consistently show greater psychological morbidity than older women after breast cancer diagnosis, there is great interest in the coping strategies of younger women. The present cross-sectional study used quantitative and qualitative methods to examine coping strategies used by 201 women who were aged 50 years or younger at diagnosis and were 6 months to 3.5 years postdiagnosis. Quantitative results from a modified version of the Ways of Coping scale revealed that the most frequently used coping strategies were positive cognitive restructuring, wishful thinking, and making changes. Qualitative analyses based on open-ended questioning of how women best coped with different stressful aspects of their diagnosis showed that women reported finding different strategies useful depending on the stressor. For example, social support was helpful in dealing with anger or depression, whereas positive cognitive restructuring was more helpful for concerns about the future. Analyses also confirmed that most coping strategies cited in commonly administered coping scales were used frequently by these women. However, several coping strategies not generally measured were also deemed valuable, including engaging in physical activity, using medications, and resting. These findings suggest that clinicians should identify patients' particular stressors and help with coping techniques targeting particular concerns.

Transcriptional regulation of the human polymeric Ig receptor gene: analysis of basal promoter elements.

Secretory Igs provide the first line of adaptive immune defense against ingested, inhaled, and sexually transmitted pathogens at mucosal surfaces. The polymeric Ig receptor regulates transport of dimeric IgA and pentameric IgM into external secretions. The level of expression of polymeric Ig receptor is controlled to a large extent by transcription of the PIGR gene in mucosal epithelial cells. Here we present a detailed analysis of the promoter of the PIGR gene by transient transfection of luciferase reporter plasmids into cultured cell lines. Comparisons of the human and mouse PIGR promoters in human and mouse intestinal and liver cell lines demonstrated that the human PIGR promoter was 4- to 5-fold more active than the mouse PIGR promoter in all cell types, and that both the human and mouse PIGR promoters were more active in intestinal than in liver cell lines. Targeted deletions of 22-bp segments of the human PIGR promoter revealed that the region from nt -63 to -84 is crucial for basal transcription, and that two upstream regions can act as positive or negative regulators. Point mutations within the region from nt -63 to -84 demonstrated that an E box motif, which binds the basic helix-loop-helix protein upstream stimulatory factor, is required for PIGR promoter activity. Two additional regulatory motifs were identified in the proximal promoter region: a binding site for AP2, and an inverted repeat motif that binds an unidentified protein. These findings suggest that cooperative binding of multiple transcription factors regulates basal activity of the human PIGR promoter.