Yap1 is required for maintenance of adult RPE differentiation.

Nuclear YAP1 plays a critical role in regulation of stem cell proliferation, tissue regeneration, and organ size in many types of epithelia. Due to rapid turnover of most epithelial cell types, the cytoplasmic function of YAP1 in epithelial cells has not been well studied. The retinal pigment epithelium (RPE) is a highly polarized epithelial cell type maintained at a senescence state, and offers an ideal cell model to study the active role of YAP1 in maintenance of the adult epithelial phenotype. Here, we show that the cytoplasmic function of YAP1 is essential to maintain adult RPE differentiation. Knockout of Yap1 in the adult mouse RPE caused cell depolarization and tight junction breakdown, and led to inhibition of RPE65 expression, diminishment of RPE pigments, and retraction of microvilli and basal infoldings. These changes in RPE further prompted the loss of adjacent photoreceptor outer segments and photoreceptor death, which eventually led to decline of visual function in older mice between 6 and 12 months of age. Furthermore, nuclear ß-catenin and its activity were significantly increased in mutant RPE. These results suggest that YAP1 plays an important role in active inhibition of Wnt/ß-catenin signaling, and is essential for downregulation of ß-catenin nuclear activity and prevention of dedifferentiation of adult RPE.

A novel POC1A variant in an alternatively spliced exon causes classic SOFT syndrome: clinical presentation of seven patients.

Biallelic pathogenic variants in POC1A are ultra rare. They have been reported in 13 families as causing either Short stature, Onychodysplasia, Facial dysmorphism, and hypoTrichosis (SOFT) syndrome, or a milder partially overlapping phenotype, variant POC1A-related syndrome. This pleiotropic effect is likely precipitated by the variant's location and respective affected protein domain. Here, we describe seven patients from two consanguineous Omani families with classic SOFT syndrome and a novel homozygous POC1A variant (c.64G>T; p.(Val22Phe)), which is the first one described for the alternative exon 2. This result refines the POC1A mutational spectrum relevant for exertion of the described pleiotropic effect. Furthermore, six of our patients experienced recurrent mild to severe respiratory difficulties that have not been previously reported for SOFT syndrome and may be an underdiagnosed or a genotype-specific complication that warrants attention in future studies. Thus, our study unravels new aspects of the genotype-phenotype correlation suggested by previous reports.

Inborn errors of metabolism in a cohort of pregnancies with non-immune hydrops fetalis: a single center experience.

OBJECTIVE: The purpose of this study was to determine the frequency of non-immune hydrops fetalis (NIHF) among all pregnancies referred for prenatal care at Sultan Qaboos University Hospital (SQUH) during the study period and to evaluate the underlying etiologies of NIH. STUDY DESIGN: All pregnancies referred to SQUH between February 2014 and December 2015 were identified, and all pregnancies meeting the diagnosis of NIHF were included in this study. All cases of NIHF referred to our center during this period underwent standard systematic diagnostic work-up that included biochemical and molecular studies in addition to the standard investigations for hydrops fetalis. Clinical characteristics and results of the diagnostic work-up were retrospectively reviewed. RESULTS: A total of 3234 pregnancies were referred for prenatal care at SQUH during the study period, and 12 pregnancies were affected by NIHF. An underlying diagnosis was established in nine cases, and the majority of cases (7/9) were caused by inborn errors of metabolism (IEM). These included a novel homozygous variant in the AARS2 gene (5/7) and two cases of galactosialidosis (2/7). CONCLUSION: IEM was a major cause of NIHF in this cohort. The AARS2 variant accounts for a significant number of cases with NIHF in this cohort of Omani patients.

Short chain fatty acids inhibit corneal inflammatory responses to TLR ligands via the ocular G-protein coupled receptor 43.

PURPOSE: Short chain fatty acids (SCFAs) produced by gut microbiota are known to play primary roles in gut homeostasis by immunomodulation partially through G-protein coupled receptors (GPR) 43. Using mouse models of TLR ligand induced keratitis, we investigated whether SCFAs and GPR43 play any regulatory roles in the pathogenesis of inflammatory responses in the eye. METHODS: Both human and mouse eyes were labeled with a specific antibody for GPR43 and imaged by a laser scanning confocal microscope. Corneal cups from naïve C57BL/6J (B6) and GPR43 knockout (KO) mice were stimulated with TLR ligands in the presence or absence of sodium butyrate overnight and then processed for RT-PCR assay for expression of GPR43 and cytokines. Keratitis was induced by Poly I:C in wild type (WT) B6, GPR43KO and chimeric mice and the disease severity was evaluated by the corneal fluorescein staining test, and infiltrating cell staining and calculating in corneal whole mount. RESULTS: GPR43 is expressed in both human and mouse eyes and the expression is bidirectionally regulated by TLR ligands and butyrate. Butyrate significantly inhibited inflammation caused by several TLR ligands such as Poly I:C, Flagellin, and CpG-ODN (TLR-3, 5 and 9 agonists, respectively) in WT, but not GPR43KO, mice. Butyrate inhibition of TLR-induced keratitis is mediated by the GPR43 expressed in tissue but not hematopoietic, cells. CONCLUSIONS: This is the first report to demonstrate of the protective effect of SCFAs on microbial keratitis, and the dynamic expression and anti-inflammatory function of GPR43 in the eye. SCFAs can modulate inflammation and immunity in the eye through GPR43.

Defining Transcriptomic Heterogeneity between Left and Right Ventricle-Derived Cardiac Fibroblasts.

Cardiac fibrosis is a key aspect of heart failure, leading to reduced ventricular compliance and impaired electrical conduction in the myocardium. Various pathophysiologic conditions can lead to fibrosis in the left ventricle (LV) and/or right ventricle (RV). Despite growing evidence to support the transcriptomic heterogeneity of cardiac fibroblasts (CFs) in healthy and diseased states, there have been no direct comparisons of CFs in the LV and RV. Given the distinct natures of the ventricles, we hypothesized that LV- and RV-derived CFs would display baseline transcriptomic differences that influence their proliferation and differentiation following injury. Bulk RNA sequencing of CFs isolated from healthy murine left and right ventricles indicated that LV-derived CFs may be further along the myofibroblast transdifferentiation trajectory than cells isolated from the RV. Single-cell RNA-sequencing analysis of the two populations confirmed that Postn+ CFs were more enriched in the LV, whereas Igfbp3+ CFs were enriched in the RV at baseline. Notably, following pressure overload injury, the LV developed a larger subpopulation of pro-fibrotic Thbs4+/Cthrc1+ injury-induced CFs, while the RV showed a unique expansion of two less-well-characterized CF subpopulations (Igfbp3+ and Inmt+). These findings demonstrate that LV- and RV-derived CFs display baseline subpopulation differences that may dictate their diverging responses to pressure overload injury. Further study of these subpopulations will elucidate their role in the development of fibrosis and inform on whether LV and RV fibrosis require distinct treatments.

Not All Proximal Humerus Fractures Do Well Without Surgery: Anterior Translation Predicts the Need for Surgery.

OBJECTIVES: To evaluate the effect of translation on a large series of low-energy proximal humerus fractures initially treated nonoperatively. DESIGN: Retrospective multicenter analysis. SETTING: Five level-one trauma centers. PATIENTS/PARTICIPANTS: Two hundred ten patients (152 F; 58 M), average age 64, with 112 left- and 98 right-sided low-energy proximal humerus fractures (OTA/AO 11-A-C). INTERVENTION: All patients were initially treated nonoperatively and were followed for an average of 231 days. Radiographic translation in the sagittal and coronal planes was measured. Patients with anterior translation were compared with those with posterior or no translation. Patients with ≥80% anterior humeral translation were compared with those with <80% anterior translation, including those with no or posterior translation. MAIN OUTCOMES: The primary outcome was failure of nonoperative treatment resulting in surgery and the secondary outcome was symptomatic malunion. RESULTS: Nine patients (4%) had surgery, 8 for nonunion and 1 for malunion. All 9 patients (100%) had anterior translation. Anterior translation compared with posterior or no sagittal plane translation was associated with failure of nonoperative management requiring surgery ( P = 0.012). In addition, of those with anterior translation, having ≥80% anterior translation compared with <80% was also associated with surgery ( P = 0.001). Finally, 26 patients were diagnosed with symptomatic malunion, of whom translation was anterior in 24 and posterior in 2 ( P = 0.0001). CONCLUSIONS: In a multicenter series of proximal humerus fractures, anterior translation of >80% was associated with failure of nonoperative care resulting in nonunion, symptomatic malunion, and potential surgery. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Report on the p.Ser489X (p.Ser489*) CFTR mutation, a variant with severe associated phenotype and high prevalence in a Quebec French-Canadian cystic fibrosis patient population.

PURPOSE: This study reports on the phenotype of cystic fibrosis patients identified to be carriers of the p.Ser489X (p.Ser489*; c.1466C>A) cystic fibrosis transmembrane conductance regulator (CFTR) mutation, a variant rarely described in the cystic fibrosis literature, as well as on its allelic frequency in a French-Canadian cystic fibrosis patient cohort. METHODS: Reported phenotypes and allelic frequency of this variant were collected based on the data from a large French-Canadian cystic fibrosis patient cohort. RESULTS: Cystic fibrosis patients found to carry the p.Ser489X variant generally presented with classic gastrointestinal manifestations of this condition in infancy. The allelic frequency of this variant was calculated to be 0.7% for this population. CONCLUSION: The p.Ser489X CFTR variant is a severe disease-causing CFTR allele that is relatively frequent in the French-Canadian cystic fibrosis patient population, warranting its inclusion into CFTR molecular testing panel for this population.

Iodoacetic acid, but not sodium iodate, creates an inducible swine model of photoreceptor damage.

Our purpose was to find a method to create a large animal model of inducible photoreceptor damage. To this end, we tested in domestic swine the efficacy of two chemical toxins, known to create photoreceptor damage in other species: Iodoacetic Acid (IAA) and Sodium Iodate (NaIO(3)). Intravenous (IV) administration of NaIO(3) up to 90 mg/kg had no effect on retinal function and 110 mg/kg was lethal. IV administration of IAA (5-20 mg/kg) produced concentration-dependent changes in visual function as measured by full-field and multi-focal electroretinograms (ffERG and mfERG), and 30 mg/kg IAA was lethal. The IAA-induced effects measured at two weeks were stable through eight weeks post-injection, the last time point investigated. IAA at 7.5, 10, and 12 mg/kg produce a concentration-dependent reduction in both ffERG b-wave and mfERG N1-P1 amplitudes compared to baseline at all post-injection times. Comparisons of dark- and light-adapted ffERG b-wave amplitudes show a more significant loss of rod relative to cone function. The fundus of swine treated with ≥10 mg/kg IAA was abnormal with thinner retinal vessels and pale optic discs, and we found no evidence of bone spicule formation. Histological evaluations show concentration-dependent outer retinal damage that correlates with functional changes. We conclude that NaIO(3,) is not an effective toxin in swine. In contrast, IAA can be used to create a rapidly inducible, selective, stable and concentration-dependent model of photoreceptor damage in swine retina. Because of these attributes this large animal model of controlled photoreceptor damage should be useful in the investigation of treatments to replace damaged photoreceptors.

Endothelial ultrastructural alterations of intramuscular capillaries in infantile mitochondrial cytopathies: "mitochondrial angiopathy".

Electron microscopy (EM) is a reliable method for diagnosing mitochondrial diseases in striated muscle biopsy in infancy. Ultrastructural alterations in mitochondria of myofibers are well documented, but there are few studies of endothelial involvement in intramuscular capillaries. Quadriceps femoris biopsies of five representative infants and toddlers, ages neonate to 3.5 years, were performed because of clinical and laboratory data consistent with mitochondrial disease without mitochondrial DNA (mtDNA) mutations and likely with nuclear DNA mutations. Pathological studies included histochemistry, EM, respiratory chain enzymatic assay and mtDNA sequencing and deletion/duplication analysis. EM demonstrated frequent and severe alterations of mitochondria in capillary endothelium. The most constant changes included: either too few or fragmented cristae; stacked and whorled cristae; paracrystallin structures that often were large and spheroid with stress fractures; closely apposed membranes of granular endoplasmic reticulum surrounding mitochondria with loss of the normal intervening layer of cytoplasm; long narrow, thin looped microvilli extending into the lumen; and thick microvilli containing large, abnormal mitochondria. We conclude that mitochondrial cytopathies in early life exhibit more severe ultrastructural alterations in the endothelium than in myofibers and that paracrystallin body structure differs, perhaps due to less rigid surrounding structures. This distribution may explain the frequent lack of prominent histochemical and biochemical abnormalities in muscle biopsies of young patients. Endothelial changes do not distinguish the genetic defects. Vascular involvement in brain contributes to cerebral lesions and neuronal death by impairment of molecular and nutrient transport and ischemia; endothelium in muscle may reflect similar changes.

Defining the role of laboratory genetic counselor.

An increasing number of genetic counselors are moving into non-clinical roles, where their primary duties do not involve direct patient contact. According to the National Society of Genetic Counselors Professional Status Survey in 2010, 23% of counselors working in non-clinical roles identified laboratory or genetic testing as their primary area of work. Using a survey, we identified 43 genetic counselors who work predominately in laboratory settings. The two primary tasks performed by participants, include acting as a customer liaison (95%) and calling out test results (88%). Nineteen participants (44.2%) also reported spending a considerable amount of time signing reports. The most prevalent areas of job satisfaction were support from laboratory directors (76.8%), autonomy (76.7%), interactions with clinicians (69.7%) and interaction with other genetics counselors (67.5%). This is the first study specifically looking at the roles of laboratory genetic counselors, which is an expanding area of genetic counseling.

2021 Bioinformatics and Translational Informatics Best Papers.

OBJECTIVES: To identify and summarize the top bioinformatics and translational informatics papers published in 2021 for the IMIA Yearbook. METHODS: We performed a broad literature search to retrieve Bioinformatics and Translational Informatics (BTI) papers and coupled this with a series of editorial and peer reviews to identity the top papers in the area. RESULTS: We identified a final candidate list of 15 BTI papers for peer-review; from these candidates, the top three papers were chosen to highlight in this synopsis. These papers expand the integration of multi-omics data with electronic health records and use advanced machine learning approaches to tailor models to individual patients. In addition, our honorable mention paper foreshadows the growing impact of BTI research on precision medicine through the continued development of large clinical consortia. CONCLUSION: In the top BTI papers this year, we observed several important trends, including the use of deep-learning approaches to analyse diverse data types, the development of integrative and web-accessible bioinformatics pipelines, and a continued focus on the power of individual genome sequencing for precision health.

Anatomical evidence of photoreceptor degeneration induced by iodoacetic acid in the porcine eye.

Iodoacetic acid (IAA) induces photoreceptor (PR) degeneration in small animal models, however, eye size and anatomic differences detract from the usefulness of these models for studying retinal rescue strategies intended for humans. Porcine eyes are closer in size to human eyes and have a rich supply of rod and cones. This study investigated whether IAA also produced PR degeneration in the porcine retina, whether the damage was preferential for rods or cones, and whether IAA induced remodeling of the inner retina. Pigs were given a single i.v. injection of IAA and were euthanized 2-5 weeks later. Eyes were enucleated and immersed in fixative. Forty-six eyes were studied: Control (n = 13), and from pigs that had received the following IAA doses: 5.0 mg/kg (n = 7); 7.5 mg/kg (n = 10); 10.0 mg/kg (n = 6); 12.0 mg/kg (n = 6). Tissue was retrieved from four retinal locations: 8 mm and 2 mm above the dorsal margin of the optic disc, and 2 mm and 8 mm below the disc, and was processed for conventional histology, immunohistochemistry, and transmission electron microscopy. At 5.0 mg/kg IAA produced mild, variable cell loss, but remaining cells exhibited normal features. At doses above 5.0 mg/kg, a dose-dependent reduction was observed in the length of PR inner and outer segments, and in the number of PR nuclei. Specific labeling revealed a massive dropout of rod cell bodies with relative sparing of cone cell bodies, and electron microscopy revealed a reduction in the number of PR synaptic terminals. Mild dendritic retraction of rod bipolar cells and hypertrophy of Müller cell stalks was also observed, although the inner nuclear layer appeared intact. The porcine IAA model may be useful for developing and testing retinal rescue strategies for human diseases in which rods are more susceptible than cones, or are affected earlier in the disease process.

SOS! Summer of Smoke: a retrospective cohort study examining the cardiorespiratory impacts of a severe and prolonged wildfire season in Canada's high subarctic.

OBJECTIVES: To determine healthcare service utilisation for cardiorespiratory presentations and outpatient salbutamol dispensation associated with 2.5 months of severe, unabating wildfire smoke in Canada's high subarctic. DESIGN: A retrospective cohort study using hospital, clinic, pharmacy and environmental data analysed using Poisson regression. SETTING: Territorial referral hospital and clinics in Yellowknife, Northwest Territories, Canada. PARTICIPANTS: Individuals from Yellowknife and surrounding communities presenting for care between 2012 and 2015. MAIN OUTCOME MEASURES: Emergency room (ER) presentations, hospital admissions and clinic visits for cardiorespiratory events, and outpatient salbutamol prescriptions RESULTS: The median 24-hour mean particulate matter (PM2.5) was fivefold higher in the summer of 2014 compared with 2012, 2013 and 2015 (median=30.8 µg/m3), with the mean peaking at 320.3 µg/m3. A 10 µg/m3 increase in PM2.5 was associated with an increase in asthma-related (incidence rate ratio (IRR) (95% CI): 1.11 (1.07, 1.14)) and pneumonia-related ER visits (IRR (95% CI): 1.06 (1.02, 1.10)), as well as an increase in chronic obstructive pulmonary disease hospitalisations (IRR (95% CI): 1.11 (1.02, 1.20). Compared with 2012 and 2013, salbutamol dispensations in 2014 increased by 48%; clinic visits for asthma, pneumonia and cough increased; ER visits for asthma doubled, with the highest rate in females, in adults aged ≥40 years and in Dene people, while pneumonia increased by 57%, with higher rates in males, in individualsaged <40 years and in Inuit people. Cardiac variables were unchanged. CONCLUSIONS: Severe wildfires in 2014 resulted in extended poor air quality associated with increases in health resource utilization; some impacts were seen disproportionately among vulnerable populations, such as children and Indigenous individuals. Public health advisories asking people to stay inside were inadequately protective, with compliance possibly impacted by the prolonged exposure. Future research should investigate use of at-home air filtration systems, clean-air shelters and public health messaging which addresses mental health and supports physical activity.

CIB2 regulates mTORC1 signaling and is essential for autophagy and visual function.

Age-related macular degeneration (AMD) is a multifactorial neurodegenerative disorder. Although molecular mechanisms remain elusive, deficits in autophagy have been associated with AMD. Here we show that deficiency of calcium and integrin binding protein 2 (CIB2) in mice, leads to age-related pathologies, including sub-retinal pigment epithelium (RPE) deposits, marked accumulation of drusen markers APOE, C3, Aß, and esterified cholesterol, and impaired visual function, which can be rescued using exogenous retinoids. Cib2 mutant mice exhibit reduced lysosomal capacity and autophagic clearance, and increased mTORC1 signaling-a negative regulator of autophagy. We observe concordant molecular deficits in dry-AMD RPE/choroid post-mortem human tissues. Mechanistically, CIB2 negatively regulates mTORC1 by preferentially binding to 'nucleotide empty' or inactive GDP-loaded Rheb. Upregulated mTORC1 signaling has been implicated in lymphangioleiomyomatosis (LAM) cancer. Over-expressing CIB2 in LAM patient-derived fibroblasts downregulates hyperactive mTORC1 signaling. Thus, our findings have significant implications for treatment of AMD and other mTORC1 hyperactivity-associated disorders.

Relationships between increased aqueous outflow facility during washout with the changes in hydrodynamic pattern and morphology in bovine aqueous outflow pathways.

Previous studies suggest that the structural correlate for the increased outflow facility (C) during washout in the bovine eye is separation between the inner wall (IW) and underlying juxtacanalicular connective tissue (JCT). However, how these structural changes affect hydrodynamic patterns of outflow during washout has not been studied. We hypothesize that an increase in the outflow facility during washout is associated with an increase in the effective filtration area (EFA) of aqueous outflow, which is regulated by a loss of the connectivity between the IW and JCT. To test this hypothesis, the relationship between C and the hydrodynamic patterns of outflow as well as the morphological changes in JCT and IW during the washout were investigated. Ten bovine eyes were perfused at 15 mmHg with Dulbecco's PBS + 5.5 mM glucose (DPBS) for 30 min to establish stable baseline C. After measuring baseline C, five eyes (short-duration group) were perfused with 0.5 mL DPBS containing 0.002% microspheres (0.5 microm) to trace the hydrodynamic pattern of outflow. Five other eyes (long-duration group) were perfused for 3 h to elicit a significant washout effect followed by subsequent perfusion of the same volume (0.5 mL) of microspheres to map out the outflow pattern after washout. All eyes were then perfusion-fixed. Anterior segments were sectioned and prepared for confocal and light microscopy. Total length (TL) and filtration length (FL) of the IW were measured in > or =15 images/eye to calculate percent effective filtration length (PEFL = FL/TL) while TL and length exhibiting JCT/IW separation (SL) were measured in > or =13 images/eye to calculate percent separation length (PSL = SL/TL). In long-duration eyes, C increased 170.5 +/- 21.3% (mean +/- SEM, 1.55 +/- 0.24 vs 4.13 +/- 0.55 microl/min/mmHg, p = 0.001) above baseline. Pre-fixation C (4.13 +/- 0.55 microl/min/mmHg) in long-duration was 1.6-fold greater than that (2.14 +/- 0.61 microl/min/mmHg; p = 0.042) in short-duration. A more uniform tracer labeling was observed in the JCT/IW of long-duration eyes compared to short-duration. PEFL was 2.3-fold larger (52.82 +/- 6.06 vs. 22.2 +/- 6.0%; p = 0.007) and PSL was 2.6-fold larger (54.2 +/- 6.0 vs. 20.5 +/- 1.3%; p = 0.004) in long-duration eyes compared to short-duration. Data from all eyes revealed a positive correlation between PEFL and PSL (p = 0.02). Both PEFL and PSL demonstrated significant positive correlations with the relative increase in C due to washout (p < or = 0.05). An additional experiment was performed in which unequal volumes of tracer (0.5 and 1.0 mL) were perfused in paired eyes for both short- and long-duration (N = 2 for each condition) to examine the affect on PEFL. No significant change in PEFL was found in eyes perfused with 0.5 and 1.0 mL within the same group. These data support our hypothesis that separations between the IW and JCT result in an increase in the EFA that then influences C. Altogether, these data suggest that outflow hydrodynamics and the tissue structure work together to regulate outflow resistance.

Underdiagnoses resulting from variant misinterpretation: Time for systematic reanalysis of whole exome data?

BACKGROUND: Clinical whole exome sequencing (WES) yields a diagnosis in approximately 30% of patients evaluated for presumed genetic disorders. For unsolved cases, periodic reanalysis is usually predicated on the availability of improved bioinformatics tools or new gene discoveries. METHODS: Exome data reanalysis was independently performed on unsolved cases that had underwent trio analysis by an external service provider. The retrieved exome data was reannotated using wANNOVAR and reanalysed following standard filtering criteria. RESULTS: Independent reanalysis led to the identification of a disease-causing variation in two families segregating predominantly a neurological phenotype. As the causative genes were relatively well established at the time the WES referral was made, misinterpretation of the functional impact of the variant and/or underappreciation of the gene's associated phenotype are the most probable causes of the discrepancy in reporting. CONCLUSION: Non-diagnostic clinical exome resulting from variant misinterpretation is probably under appreciated. These results emphasise the relevance of implement a policy for the reanalysis of high-throughput sequencing data, especially in a clinical context given the implications.

Spinocerebellar ataxia with axonal neuropathy type 1 revisited.

Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1; OMIM #607250), an exceedingly rare disorder having been documented in only a single family from Saudi Arabia, is the result of an unusual mutation in the tyrosyl DNA phosphodiesterase 1 gene (TDP1). We performed high-throughput sequencing (whole exome and ataxia gene panel) in two apparently unrelated Omani families segregating sensorimotor neuropathy and ataxia in an autosomal recessive fashion. Following validation by Sanger sequencing, all affected subjects (n = 4) were confirmed to carry the known SCAN1 pathogenic homozygous variant in the TDP1 gene, NM_001008744.1:c.1478A > G (p.His493Arg). In keeping with the initial description, our patients demonstrated progressive ataxia, cerebellar atrophy and disabling axonal sensori-motor neuropathy (n = 4), hypercholesterolemia (n = 2) and elevated serum alpha fetoprotein (n = 3). In addition, our patients also had mild cognitive deficits in multiple domains (n = 3), a feature not previously reported. Our findings independently revalidate the phenotype of TDP1 mutation and expand the clinical spectrum to include mild cognitive deficits. Haplotype sharing, as determined by DNA microarray (CytoScan HD), attests to a possible common founder mutation in the Arab population.

Metabolic Deregulation of the Blood-Outer Retinal Barrier in Retinitis Pigmentosa.

Retinitis pigmentosa (RP) initiates with diminished rod photoreceptor function, causing peripheral and night-time vision loss. However, subsequent loss of cone function and high-resolution daylight and color vision is most debilitating. Visual pigment-rich photoreceptor outer segments (OS) undergo phagocytosis by the retinal pigment epithelium (RPE), and the RPE also acts as a blood-outer retinal barrier transporting nutrients, including glucose, to photoreceptors. We provide evidence that contact between externalized phosphatidylserine (PS) on OS tips and apical RPE receptors activates Akt, linking phagocytosis with glucose transport to photoreceptors for new OS synthesis. As abundant mutant rod OS tips shorten in RP, Akt activation is lost, and onset of glucose metabolism in the RPE and diminished glucose transport combine to cause photoreceptor starvation and accompanying retinal metabolome changes. Subretinal injection of OS tip mimetics displaying PS restores Akt activation, glucose transport, and cone function in end-stage RP after rods are lost.