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1.
World Neurosurg ; 182: e772-e779, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38092350

ABSTRACT

OBJECTIVE: To identify variables that may contribute to the development of proximal junctional failure (PJF) in patients with long lumbo-sacral and thoraco-lumbo-pelvic constructs undergoing anterior column realignment (ACR) with anterior longitudinal ligament release (ALLR). METHODS: Data of patients with adult spinal deformity who underwent ACR with ALLR at L3-4 were collected retrospectively from medical records and a prospectively maintained spine research database between 2016 and 2022. RESULTS: Eleven (41%) developed PJF at a mean of 24 ± 21 months from the index surgery. The cohort was then divided into 2 groups for analysis, 13 subjects in the high pelvic incidence (PI) group (defined as PI ≥ 55°) and 14 subjects in the low PI group (defined as PI < 55°). Visual Analog Scale for back pain and Oswestry Disability Index decreased from 9.5 to 2.1 and 61 to 10 in the high PI group, and from 8.9 to 2.4 and 60.9 to 10.3 in the low PI group, respectively. PI (P = 0.004), sacral slope (P = 0.005), and postoperative PI-lumbar lordosis mismatch (P = 0.02) were found to be significant predictors of PJF. The receiver operator curve revealed a cutoff PI value ≤ 53° (95% confidence interval: 52°-64°), below which the risk of PJF becomes significantly higher in patients undergoing ACR with ALLR at L3-4. CONCLUSIONS: PI may be a predictor of PJF and highly correlates with ACR-ALLR levels. In patients undergoing L3-4 ACR-ALLR, a PI value of ≤53° is associated with a significantly elevated risk of PJF. Preoperative planning of ACR-ALLR level based on normal sagittal alignment in otherwise healthy individuals may mitigate the risk of PJF development in patients with adult spinal deformity treated with ACR-ALLR.


Subject(s)
Kyphosis , Lordosis , Spinal Fusion , Adult , Humans , Lordosis/diagnostic imaging , Lordosis/surgery , Lordosis/etiology , Retrospective Studies , Longitudinal Ligaments/surgery , Spinal Fusion/adverse effects , Sacrum , Kyphosis/surgery , Postoperative Complications/epidemiology , Lumbar Vertebrae/diagnostic imaging , Lumbar Vertebrae/surgery
2.
BMJ Open ; 13(11): e075480, 2023 11 27.
Article in English | MEDLINE | ID: mdl-38011969

ABSTRACT

PURPOSE: Patient-reported outcome measures (PROMs) are useful for trauma registries interested in monitoring patient outcomes and trauma care quality. PROMs had not previously been collected by the New Zealand Trauma Registry (NZTR). More than 2500 New Zealanders are admitted to hospital for major trauma annually. The Trauma Outcomes Project (TOP) collected PROMs postinjury from three of New Zealand's (NZ's) major trauma regions. This cohort profile paper aims to provide a thorough description of preinjury and 6 month postinjury characteristics of the TOP cohort, including specifically for Maori (Indigenous population in Aotearoa me Te Waipounamu/NZ). PARTICIPANTS: Between July 2019 and June 2020, 2533 NZ trauma patients were admitted to one of 22 hospitals nationwide for major trauma and included on the NZTR. TOP invited trauma patients (aged ≥16 years) to be interviewed from three regions; one region (Midlands) declined to participate. Interviews included questions about health-related quality of life, disability, injury recovery, healthcare access and household income adequacy. FINDINGS TO DATE: TOP recruited 870 participants, including 119 Maori. At 6 months postinjury, most (85%) reported that the injury still affected them, 88% reported problems with≥1 of five EQ-5D-5L dimensions (eg, 75% reported problems with pain or discomfort, 71% reported problems with usual activities and 52% reported problems with mobility). Considerable disability (World Health Organization Disability Assessment Schedule, WHODAS II, score ≥10) was reported by 45% of participants. The prevalence of disability among Maori participants was 53%; for non-Maori it was 44%. Over a quarter of participants (28%) reported trouble accessing healthcare services for their injury. Participation in paid work decreased from 63% preinjury to 45% 6 months postinjury. FUTURE PLANS: The 12 and 24 month postinjury data collection has recently been completed; analyses of 12 month outcomes are underway. There is potential for longer-term follow-up interviews with the existing cohort in future. TOP findings are intended to inform the National Trauma Network's quality improvement processes. TOP will identify key aspects that aid in improving postinjury outcomes for people experiencing serious injury, including importantly for Maori.


Subject(s)
Delivery of Health Care , Maori People , Quality of Life , Wounds and Injuries , Humans , Hospitalization/statistics & numerical data , Maori People/statistics & numerical data , New Zealand/epidemiology , Prospective Studies , Wounds and Injuries/epidemiology , Wounds and Injuries/ethnology , Wounds and Injuries/therapy , Patient Reported Outcome Measures , Adolescent , Adult , Young Adult , Delivery of Health Care/economics , Delivery of Health Care/ethnology , Delivery of Health Care/statistics & numerical data
3.
Oper Neurosurg (Hagerstown) ; 25(2): 136-141, 2023 08 01.
Article in English | MEDLINE | ID: mdl-37163706

ABSTRACT

BACKGROUND: Adjacent segment disease (ASD) is a common problem after lumbar spinal fusions. Ways to reduce the rates of ASD are highly sought after to reduce the need for reoperation. OBJECTIVE: To find predisposing factors of ASD after lumbar interbody fusions, especially in mismatch of pelvic incidence and lumbar lordosis (PI-LL). METHODS: We conducted a retrospective cohort study of all patients undergoing lumbar interbody fusions of less than 4 levels from June 2015 to July 2020 with at least 1 year of follow-up and in those who had obtained postoperative standing X-rays. RESULTS: We found 243 patients who fit inclusion and exclusion criteria. Fourteen patients (5.8%) developed ASD, at a median of 24 months. Postoperative lumbar lordosis was significantly higher in the non-ASD cohort (median 46.4° ± 1.4° vs 36.9° ± 3.6°, P < .001), pelvic tilt was significantly lower in the non-ASD cohort (16.0° ± 0.66° vs 20.3° ± 2.4°, P = .002), PI-LL mismatch was significantly lower in the non-ASD cohort (5.28° ± 1.0° vs 17.1° ± 2.0°, P < .001), and age-appropriate PI-LL mismatch was less common in the non-ASD cohort (34 patients [14.8%] vs 13 [92.9%] of patients with high mismatch, P < .001). Using multivariate analysis, greater PI-LL mismatch was predictive of ASD (95% odds ratio CI = 1.393-2.458, P < .001) and age-appropriate PI-LL mismatch was predictive of ASD (95% odds ratio CI = 10.8-970.4, P < .001). CONCLUSION: Higher PI-LL mismatch, both age-independent and when adjusted for age, after lumbar interbody fusion was predictive for developing ASD. In lumbar degenerative disease, correction of spinopelvic parameters should be a main goal of surgical correction.


Subject(s)
Lordosis , Humans , Lordosis/diagnostic imaging , Lordosis/surgery , Retrospective Studies , Lumbar Vertebrae/diagnostic imaging , Lumbar Vertebrae/surgery , Postoperative Complications/diagnostic imaging , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Risk Factors
5.
Injury ; 2023 Mar 11.
Article in English | MEDLINE | ID: mdl-36931967

ABSTRACT

INTRODUCTION: Understanding predictors of hospital readmission following major trauma is important as readmissions are costly and some are potentially avoidable. This study describes the incidence of, and sociodemographic, injury-related and treatment-related factors predictive of, hospital readmission related to: a) all-causes, b) the index trauma injury, and c) subsequent injury events in the 30 days and 12 months following discharge for major trauma patients nationally in New Zealand. METHODS: Data from the New Zealand Trauma Registry (NZTR) was linked with Ministry of Health hospital discharge data. Hospital readmissions were examined for all patients entered into the NZTR for an injury event between 1 January and 31 December 2018. Readmissions were examined for the 12-months following the discharge date for participant's index trauma injury. RESULTS: Of 1986 people, 42% had ≥1 readmission in the 12 months following discharge; 15% within 30 days. Seven percent had ≥1 readmission related to the index trauma within 30 days of discharge; readmission was 3.43 (95% CI 1.87, 6.29) times as likely if the index trauma was self-inflicted compared to unintentional, and 1.64 (95% CI 1.15, 2.34) times as likely if the index trauma involved intensive care unit admission. Those admitted to hospital for longer for their index trauma were less likely to be readmitted due to their index trauma injury within 30 days compared to those admitted for 0-1 day. Seventeen percent were readmitted for a subsequent injury event within 12 months, with readmission more likely for older people (>65 years), those with comorbidities, Maori compared with non-Maori and those with higher trauma injury severity. CONCLUSION: A substantial proportion of people are readmitted after discharge for major trauma. Factors identified in this study will be useful to consider when developing interventions to reduce preventable readmissions including those related to the index trauma injury, readmissions from other causes and subsequent injury-related readmissions. Further research specifically examining planned and unplanned readmissions is warranted.

6.
Emerg Med Australas ; 35(1): 25-33, 2023 02.
Article in English | MEDLINE | ID: mdl-35859101

ABSTRACT

OBJECTIVE: The aim of the present study was to obtain an unbiased understanding of the prevalence of psychoactive drugs in trauma patients presenting to a large ED. METHODS: Consecutive adult patients presenting to the ED with an injury resulting in a trauma call had an anonymised, additional blood test taken for detection of over 2000 drugs. Laboratory testing was to judicial standards. Drugs given by ambulance pre-hospital were detected but excluded from the analysis. RESULTS: Over 6 months 276 (74.7%) of 371 patients were tested. Of the 276 patients tested, 158 (57.2%) had one or more psychoactive drug present. Recreational drugs were detected in 101 (36.6%) patients and medicinal drugs in 88 (31.8%) patients, with a combination of both detected in 31 (11.2%) patients. The most common drugs detected were cannabis (22.1%), antidepressants (18.4%), alcohol (15.5%), opioids (10.1%), benzodiazepine/z-drugs (9.4%) and methamphetamine (7.2%). The prevalence of psychoactive drugs differed by age group, sex and cause of injury. CONCLUSIONS: The prevalence of psychoactive drugs in injury presentations to an ED is high, and provides an opportunity to reduce harm. The present study demonstrates the feasibility of an approach which limits bias and obtains results that accurately reflect the drug prevalence in injured cohorts. Systematic testing of injured patients is an important contribution to the epidemiology of injury.


Subject(s)
Illicit Drugs , Substance-Related Disorders , Adult , Humans , Substance-Related Disorders/epidemiology , Substance-Related Disorders/diagnosis , Prevalence , Illicit Drugs/adverse effects , Psychotropic Drugs/adverse effects , Emergency Service, Hospital
7.
N Z Med J ; 135(1563): 62-69, 2022 10 07.
Article in English | MEDLINE | ID: mdl-36201731

ABSTRACT

AIMS: The aims of this study were to quantify the burden, and the cost of health loss, following hospitalisation for major trauma in New Zealand. METHOD: Hospitalised major trauma patients injured between July 2017 and June 2020 were extracted from the New Zealand Trauma Registry. Case-mix of major trauma in each year was summarised using descriptive statistics. Disability-adjusted life years (DALYs) were calculated for the cohort. A cost per DALY was applied to estimate the cost of health loss. RESULTS: A total of 6,629 major trauma cases were recorded, rising from 2,072 in 2017-2018 to 2,191 in 2019-2020. The patient case-mix remained relatively consistent over the timeframe while the in-hospital mortality rate declined from 9.2% to 7.3%. Hospitalised major trauma patients accrued 22,718 DALYs (average 7,573 DALYs per year) at an estimated health loss cost of $1.02 billion ($341 million per year). The cost of health loss per case declined from $162,747 in 2017-2018 to $143,577 in 2019-2020. CONCLUSION: The burden of major trauma is high. As injury is a preventable condition, the findings highlight the need for dedicated investment in both primary prevention and trauma care in New Zealand to reduce these avoidable costs.


Subject(s)
Disability-Adjusted Life Years , Global Health , Health Care Costs , Humans , New Zealand/epidemiology , Quality-Adjusted Life Years
8.
World J Surg ; 46(12): 2850-2857, 2022 12.
Article in English | MEDLINE | ID: mdl-36064869

ABSTRACT

BACKGROUND: Comparing trauma registry data from different countries can help to identify possible differences in epidemiology, which may help to improve the care of trauma patients. METHODS: This study directly compares the incidence, mechanisms of injuries and mortality of severe TBI based on population-based data from the two national trauma registries from New Zealand and Norway. All patients prospectively registered with severe TBI in either of the national registries for the 4-year study period were included. Patient and injury variables were described and age-adjusted incidence and mortality rates were calculated. RESULTS: A total of 1378 trauma patients were identified of whom 751 (54.5%) from New Zealand and 627 (45.5%) from Norway. The patient cohort from New Zealand was significantly younger (median 32 versus 53 years; p < 0.001) and more patients from New Zealand were injured in road traffic crashes (37% versus 13%; p < 0.001). The age-adjusted incidence rate of severe TBI was 3.8 per 100,000 in New Zealand and 2.9 per 100,000 in Norway. The age-adjusted mortality rates were 1.5 per 100,000 in New Zealand and 1.2 per 100,000 in Norway. The fatality rates were 38.5% in New Zealand and 34.2% in Norway (p = 0.112). CONCLUSIONS: Road traffic crashes in younger patients were more common in New Zealand whereas falls in elderly patients were the main cause for severe TBI in Norway. The age-adjusted incidence and mortality rates of severe TBI among trauma patients are similar in New Zealand and Norway. The fatality rates of severe TBI are still considerable with more than one third of patients dying.


Subject(s)
Brain Injuries, Traumatic , Humans , Aged , Incidence , Cohort Studies , New Zealand/epidemiology , Brain Injuries, Traumatic/epidemiology , Hospital Mortality
9.
J Neurosurg Case Lessons ; 3(5)2022 Jan 31.
Article in English | MEDLINE | ID: mdl-36130567

ABSTRACT

BACKGROUND: Gangliogliomas are well-differentiated, slow-growing glioneuronal neoplasms frequently reported to harbor upregulating alterations in the mitogen-activated protein kinase pathway, particularly serine-threonine protein kinase B-RAF alterations. Fusions involving neurotrophin tyrosine receptor kinase (NTRK) genes have rarely been reported in ganglioglioma. Similarly, echinoderm microtubule-associated protein-like (EML) 4 gene fusion has been described in lung cancer, but none has been reported in ganglioglioma. OBSERVATIONS: This report discusses the care of a 72-year-old man presenting with medication-refractory, left-sided focal seizures who was found to have a nongadolinium-enhancing, T2-hyperintense, right frontoparietal lesion. The patient received resection, and histological analysis found a World Health Organization grade I ganglioglioma, with genetic analysis demonstrating an EML4-NTRK3 gene fusion protein. LESSONS: To our knowledge, this is the first report of an NTRK3 fusion, EML4-NTRK3, in an adult ganglioglioma, which is otherwise mostly associated with BRAF alterations and activation of the mitogen-activated protein kinase signaling pathway. Further studies are needed to elucidate the function of the resultant fusion protein and determine whether it may serve as a future therapeutic target.

10.
Clin Spine Surg ; 35(3): E351-E355, 2022 04 01.
Article in English | MEDLINE | ID: mdl-34629387

ABSTRACT

STUDY DESIGN: This was a retrospective cohort study. OBJECTIVE: While intraoperative neuromonitoring (IONM) has been increasingly used in spine surgery to have a real-time evaluation of the neurological injury, we aim here to assess its utility during anterior lumbar interbody fusion (ALIF) and its association with postoperative neurological deficit. SUMMARY OF BACKGROUND DATA: ALIF is a beneficial surgical approach for patients with degenerative disease of the lower lumbar spine who would benefit from increased lordosis and restoration of neuroforaminal height. One risk of ALIF is iatrogenic nerve root injury. IONM may be useful in preventing this injury. MATERIALS AND METHODS: We performed a retrospective cohort study of 111 consecutive patients who underwent ALIF at a tertiary care academic center by 6 spine surgeons. We aimed to describe the association between IONM, postoperative weakness, and factors that predispose our center to using IONM. RESULTS: The 111 patients had a median age of 62 years [interquartile range (IQR): 53-69 y]. Neuromonitoring was used in 67 patients (60.3%) and not used in 44 patients. Seven neuromonitoring patients had IONM changes during the surgery. Three of these patients' surgeries featured intraoperative adjustments to reduce iatrogenic neural injury. The IONM cohort underwent significantly more complex procedures [5 levels (IQR: 3-7) vs. 2 levels (IQR: 2-5), P=0.001]. There was no difference in rates of new or worsened postoperative weakness (IONM: 20.6%, non-IONM: 20.5%). CONCLUSIONS: We demonstrate evidence of the potential benefits of IONM for patients undergoing ALIF. Intraoperative changes in neuromonitoring signals resulted in surgical adjustments that likely prevented neurological deficits postoperatively. IONM was protective so that more complex surgeries did not have a higher rate of postoperative weakness.


Subject(s)
Lumbosacral Region , Spinal Fusion , Humans , Lumbar Vertebrae/surgery , Middle Aged , Neurosurgical Procedures , Retrospective Studies , Spinal Fusion/adverse effects , Spinal Fusion/methods
12.
J Neurol Surg B Skull Base ; 82(4): 466-475, 2021 Aug.
Article in English | MEDLINE | ID: mdl-35573927

ABSTRACT

Background Transpetrosal approaches have become standard technique for resection of petroclival meningiomas (PCM). The retrosigmoid craniotomy has also been extensively studied as an alternative approach. The need to resect the tentorium at the end of a retrosigmoid approach has been described, but the upfront transtentorial variation of the retrosigmoid craniotomy has never been described nor evaluated in detail as a possible alternative to the standard petrosectomy approaches. Objective This study was aimed to directly compare the transpetrosal approaches to the retrosigmoid transtentorial approach (RSTTA) in terms of degree of resection, duration of surgery, and estimated blood loss (EBL). Methods A retrospective case-control study of patients who underwent resection of PCM between January 2014 and December 2018 was performed. Patients in the two surgical approach groups were matched for age and tumor location. The primary measured outcomes were duration of surgery, EBL, extent of resection, length of postoperative hospital stay, and complications. Data analysis was performed using analysis of variance (ANOVA), multivariate analysis of variance (MANOVA), and analysis of covariance (ANCOVA) tests. Results Thirteen patients had microsurgical resection of PCM at our center between January 2014 and December 2018. Nine patients underwent a transpetrosal approach and four patients underwent RSTTA. The average duration of surgery was shorter in the RSTTA group (425 vs. 525.4 minutes) and had less blood loss (94 vs. 425 mL). Extent of resection was comparable between the groups. Conclusion The RSTTA appears to be a safe and efficient technique for resecting PCMs and in selected cases a valid alternative to standard petrosectomies approaches.

13.
Surg Neurol Int ; 7: 52, 2016.
Article in English | MEDLINE | ID: mdl-27213106

ABSTRACT

BACKGROUND: The authors present the unique case of a dural-based, infantile hemangioma located in the posterior fossa of a 15-day-old infant. CASE DESCRIPTION: The patient presented with hydrocephalus. The lesion was identified by magnetic resonance imaging and was subsequently resected. Diagnosis of the lesion was confirmed with immunohistochemistry staining. The patient's hospital course was complicated by transverse sinus thrombosis and a cerebrospinal fluid leak that were treated with anticoagulation therapy and ventriculoperitoneal shunt placement, respectively. CONCLUSION: Although hemangiomas are benign entities, our patient's lesion was in the posterior fossa causing compression and hydrocephalus that necessitated resection. We encourage others to consider the possibility of hemangioma in the differential diagnosis of dural-based posterior fossa lesions in infants.

14.
AoB Plants ; 62014 Sep 23.
Article in English | MEDLINE | ID: mdl-25249265

ABSTRACT

The relationship between net primary productivity (NPP) and species richness has been the subject of long-running debate. A changing climate gives added impetus to resolving this debate, as it becomes increasingly necessary to predict biodiversity responses that might arise from shifts in productivity or its climatic correlates. It has become increasingly clear that at small scales productivity-species richness relationships (PSRs) are variable, while at macro scales relationships are typically positive. We demonstrate the importance of explicitly considering scale in discussions on PSRs even at large scales by showing that distinct patterns emerge in a global dataset of terrestrial ecoregions when ecoregions are binned into size classes. At all sizes, PSRs in ecoregions are positive, but the strength of the PSR scales positively with ecoregion size. In small ecoregions (10(3)-10(4) km(2)), factors correlating with productivity play only a minor role in species richness patterns, while in large ecoregions (>10(5) km(2)), NPP modelled from remotely sensed data is able to explain most of the variation in species richness. Better understanding the effects of scale on PSRs contributes to the debate on the relationship between species richness and productivity, which in turn allows us to better predict how both long- and short-term biodiversity patterns and ecosystem functioning might be altered under global change scenarios. This gives focus on future research to clarify causal pathways between species richness and productivity with appropriate attention to scale as an important focusing element.

15.
Dev Biol ; 373(2): 431-41, 2013 Jan 15.
Article in English | MEDLINE | ID: mdl-22960038

ABSTRACT

Growth Factor Independence (Gfi) transcription factors play essential roles in hematopoiesis, differentially activating and repressing transcriptional programs required for hematopoietic stem/progenitor cell (HSPC) development and lineage specification. In mammals, Gfi1a regulates hematopoietic stem cells (HSC), myeloid and lymphoid populations, while its paralog, Gfi1b, regulates HSC, megakaryocyte and erythroid development. In zebrafish, gfi1aa is essential for primitive hematopoiesis; however, little is known about the role of gfi1aa in definitive hematopoiesis or about additional gfi factors in zebrafish. Here, we report the isolation and characterization of an additional hematopoietic gfi factor, gfi1b. We show that gfi1aa and gfi1b are expressed in the primitive and definitive sites of hematopoiesis in zebrafish. Our functional analyses demonstrate that gfi1aa and gfi1b have distinct roles in regulating primitive and definitive hematopoietic progenitors, respectively. Loss of gfi1aa silences markers of early primitive progenitors, scl and gata1. Conversely, loss of gfi1b silences runx-1, c-myb, ikaros and cd41, indicating that gfi1b is required for definitive hematopoiesis. We determine the epistatic relationships between the gfi factors and key hematopoietic transcription factors, demonstrating that gfi1aa and gfi1b join lmo2, scl, runx-1 and c-myb as critical regulators of teleost HSPC. Our studies establish a comparative paradigm for the regulation of hematopoietic lineages by gfi transcription factors.


Subject(s)
DNA-Binding Proteins/genetics , Gene Expression Regulation, Developmental , Hematopoiesis/genetics , Zebrafish Proteins/genetics , Zebrafish/genetics , Amino Acid Sequence , Animals , Cloning, Molecular , Conserved Sequence/genetics , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/metabolism , Embryo, Nonmammalian/metabolism , Epistasis, Genetic , Erythropoiesis/genetics , Evolution, Molecular , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/metabolism , Hematopoietic System/embryology , Hematopoietic System/metabolism , Models, Biological , Molecular Sequence Data , Zebrafish/embryology , Zebrafish Proteins/chemistry , Zebrafish Proteins/metabolism
16.
Ecology ; 93(10): 2241-52, 2012 Oct.
Article in English | MEDLINE | ID: mdl-23185885

ABSTRACT

The nature of the relationship between productivity and species richness has remained controversial for at least two decades. Recently authors have favored the suggestion that the form of this relationship is highly variable and scale dependent. However, this conclusion is not universally accepted. Here we present the results of a meta-analysis of animal productivity-species-richness relationships (PSRR) in terrestrial and freshwater ecosystems. Initially, 374 separate cases from 273 published studies were identified as potential tests of the animal PSRR. After critically assessing each study, 115 cases were accepted as robust tests of the relationship, and of these 95 had data available for formal meta-analysis. Contrary to expectation, we found no support for the form of the relationship being scale dependent; positive relationships predominated at all scales (geographical extents and grains). Furthermore, positive relationships were the most common form of the animal PSRR in both terrestrial and freshwater ecosystems and among vertebrates, invertebrates, homeotherms and poikilotherms. Therefore, our results also contrast with previous reviews that suggest no particular form of the PSRR is predominant. We demonstrate that the method used for classifying the form of PSRRs is critical to the result and that previous reviews may have been too liberal toward classifying the form of relationships as unimodal. The tendency for positive relationships between productivity and species richness across diverse animal taxa has important implications for understanding the mechanisms behind the latitudinal gradient in species richness.


Subject(s)
Biodiversity , Plants/metabolism , Animals , Demography
17.
Am J Hum Genet ; 90(1): 40-8, 2012 Jan 13.
Article in English | MEDLINE | ID: mdl-22226084

ABSTRACT

Ocular coloboma is a developmental defect of the eye and is due to abnormal or incomplete closure of the optic fissure. This disorder displays genetic and clinical heterogeneity. Using a positional cloning approach, we identified a mutation in the ATP-binding cassette (ABC) transporter ABCB6 in a Chinese family affected by autosomal-dominant coloboma. The Leu811Val mutation was identified in seven affected members of the family and was absent in six unaffected members from three generations. A LOD score of 3.2 at θ = 0 was calculated for the mutation identified in this family. Sequence analysis was performed on the ABCB6 exons from 116 sporadic cases of microphthalmia with coloboma (MAC), isolated coloboma, and aniridia, and an additional mutation (A57T) was identified in three patients with MAC. These two mutations were not present in the ethnically matched control populations. Immunostaining of transiently transfected, Myc-tagged ABCB6 in retinal pigment epithelial (RPE) cells showed that it localized to the endoplasmic reticulum and Golgi apparatus of RPE cells. RT-PCR of ABCB6 mRNA in human cell lines and tissue indicated that ABCB6 is expressed in the retinae and RPE cells. Using zebrafish, we show that abcb6 is expressed in the eye and CNS. Morpholino knockdown of abcb6 in zebrafish produces a phenotype characteristic of coloboma and replicates the clinical phenotype observed in our index cases. The knockdown phenotype can be corrected with coinjection of the wild-type, but not mutant, ABCB6 mRNA, suggesting that the phenotypes observed in zebrafish are due to insufficient abcb6 function. Our results demonstrate that ABCB6 mutations cause ocular coloboma.


Subject(s)
ATP-Binding Cassette Transporters/genetics , Coloboma/genetics , Mutation , ATP-Binding Cassette Transporters/biosynthesis , Animals , Asian People/genetics , Base Sequence , Cell Line , Central Nervous System/metabolism , Exons , Eye Abnormalities/genetics , Female , Humans , Lod Score , Male , Microphthalmos/genetics , Middle Aged , Molecular Sequence Data , Morpholinos/administration & dosage , Retinal Pigment Epithelium , Transfection , Zebrafish , Zebrafish Proteins/genetics
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