Common polymorphisms in the first intron of FTO are associated with increased body weight in adults. Previous studies have suggested that a CUX1-regulatory element within the implicated FTO region ...controls expression of FTO and the nearby ciliary gene, RPGRIP1L. Given the role of ciliary genes in energy homeostasis, we hypothesized that mice hypomorphic for Rpgrip1l would display increased adiposity. We find that Rpgrip1l+/− mice are hyperphagic and fatter, and display diminished suppression of food intake in response to leptin administration. In the hypothalamus of Rpgrip1l+/− mice, and in human fibroblasts with hypomorphic mutations in RPGRIP1L, the number of AcIII-positive cilia is diminished, accompanied by impaired convening of the leptin receptor to the vicinity of the cilium, and diminished pStat3 in response to leptin. These findings suggest that RPGRIP1L may be partly or exclusively responsible for the obesity susceptibility signal at the FTO locus.
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•Mice heterozygous for a null Rpgrip1l allele are fatter than wild-type controls•Leptin signaling is diminished in the hypothalami of Rpgrip1l+/− mice•The localization of the leptin receptor is perturbed in Rpgrip1l+/− mice•RPGRIP1L may account for part or all of the association of the FTO locus with BMI
Common polymorphisms in the first intron of the Fat Mass and Obesity-Associated (FTO) gene are linked with increased body weight in adults. Stratigopoulos et al. show that the nearby ciliary gene, RPGRIP1L, could be responsible for the obesity susceptibility signal at the FTO locus.
In order to develop a practical engineering tool for predicting the relative growth rates and morphology of solution-grown faceted crystals, a method for quickly determining solvent-modified crystal ...surface energies is required. The bulk interface approximation and model by van Oss, Chaudhury, and Good provides the most practical option available for small organic molecules. Applying these techniques to the mechanistic growth modeling of four centrosymmetric crystal systems provides evidence of the utility of this treatment, since both sublimation and solution growth shape predictions correspond to experimental shapes. The fact that the approach correctly predicts the changes between sublimation and solution growth shapes supports the ability of this technique to accurately account for the solvent effect.
Nephronophthisis (NPHP), Joubert (JBTS), and Meckel-Gruber (MKS) syndromes are autosomal-recessive ciliopathies presenting with cystic kidneys, retinal degeneration, and cerebellar/neural tube ...malformation. Whether defects in kidney, retinal, or neural disease primarily involve ciliary, Hedgehog, or cell polarity pathways remains unclear. Using high-confidence proteomics, we identified 850 interactors copurifying with nine NPHP/JBTS/MKS proteins and discovered three connected modules: “NPHP1-4-8” functioning at the apical surface, “NPHP5-6” at centrosomes, and “MKS” linked to Hedgehog signaling. Assays for ciliogenesis and epithelial morphogenesis in 3D renal cultures link renal cystic disease to apical organization defects, whereas ciliary and Hedgehog pathway defects lead to retinal or neural deficits. Using 38 interactors as candidates, linkage and sequencing analysis of 250 patients identified
ATXN10 and
TCTN2 as new NPHP-JBTS genes, and our
Tctn2 mouse knockout shows neural tube and Hedgehog signaling defects. Our study further illustrates the power of linking proteomic networks and human genetics to uncover critical disease pathways.
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► High-confidence proteomics identifies an NPHP-JBTS-MKS interaction network ► Three connected modules at apical surface, at centrosomes, or linked to Hh signaling ►
ATXN10 and
TCTN2 are new NPHP-JBTS genes ►
Tctn2 mouse knockout shows neural tube and Hedgehog signaling defects
Joubert syndrome is a genetically heterogeneous ciliopathy associated with >30 genes. The characteristics of kidney disease and genotype-phenotype correlations have not been evaluated in a large ...cohort at a single center.
We evaluated 97 individuals with Joubert syndrome at the National Institutes of Health Clinical Center using abdominal ultrasonography, blood and urine chemistries, and DNA sequencing.
Patients were ages 0.6-36 years old (mean of 9.0±7.6 years old); 41 were female. Mutations were identified in 19 genes in 92 patients; two thirds of the mutations resided in six genes:
,
,
,
,
, and
. Kidney disease was detected in 30%, most commonly in association with the following genes:
(six of six),
(11 of 22), and
(three of six). No kidney disease was identified in patients with mutations in
(zero of 15) or
(zero of six). Prenatal ultrasonography of kidneys was normal in 72% of patients with kidney disease. Specific types of kidney disease included nephronophthisis (31%), an overlap phenotype of autosomal recessive polycystic kidney disease/nephronophthisis (35%), unilateral multicystic dysplastic kidney (10%), and indeterminate-type cystic kidney disease (24%). Early-onset hypertension occurred in 24% of patients with kidney disease. Age at ESRD (
=13) ranged from 6 to 24 years old (mean of 11.3±4.8 years old).
Kidney disease occurs in up to one third of patients with Joubert syndrome, most commonly in those with mutations in
,
, and
. Patients with mutations in
or
are less likely to develop kidney disease. Prenatal ultrasonography is a poor predictor of kidney involvement in Joubert syndrome. Unilateral multicystic dysplastic kidney and autosomal recessive polycystic kidney disease-like enlarged kidneys with early-onset hypertension can be part of the Joubert syndrome kidney phenotype.
Tubulin glutamylation is a post-translational modification that occurs predominantly in the ciliary axoneme and has been suggested to be important for ciliary function. However, its relationship to ...disorders of the primary cilium, termed ciliopathies, has not been explored. Here we mapped a new locus for Joubert syndrome (JBTS), which we have designated as JBTS15, and identified causative mutations in CEP41, which encodes a 41-kDa centrosomal protein. We show that CEP41 is localized to the basal body and primary cilia, and regulates ciliary entry of TTLL6, an evolutionarily conserved polyglutamylase enzyme. Depletion of CEP41 causes ciliopathy-related phenotypes in zebrafish and mice and results in glutamylation defects in the ciliary axoneme. Our data identify CEP41 mutations as a cause of JBTS and implicate tubulin post-translational modification in the pathogenesis of human ciliary dysfunction.
Joubert syndrome (JS) is a genetically and clinically heterogeneous ciliopathy characterized by distinct cerebellar and brainstem malformations resulting in the diagnostic "molar tooth sign" on brain ...imaging. To date, more than 30 JS genes have been identified, but these do not account for all patients.
In our cohort of 100 patients with JS from 86 families, we prospectively performed extensive clinical evaluation and provided molecular diagnosis using a targeted 27-gene Molecular Inversion Probes panel followed by whole-exome sequencing (WES).
We identified the causative gene in 94% of the families; 126 (27 novel) unique potentially pathogenic variants were found in 20 genes, including KIAA0753 and CELSR2, which had not previously been associated with JS. Genotype-phenotype correlation revealed the absence of retinal degeneration in patients with TMEM67, C5orf52, or KIAA0586 variants. Chorioretinal coloboma was associated with a decreased risk for retinal degeneration and increased risk for liver disease. TMEM67 was frequently associated with kidney disease.
In JS, WES significantly increases the yield for molecular diagnosis, which is essential for reproductive counseling and the option of preimplantation and prenatal diagnosis as well as medical management and prognostic counseling for the age-dependent and progressive organ-specific manifestations, including retinal, liver, and kidney disease.Genet Med advance online publication 26 January 2017.
Joubert syndrome (JS) is caused by mutations in >34 genes that encode proteins involved with primary (nonmotile) cilia and the cilium basal body. This study describes the varying ocular phenotypes in ...JS patients, with correlation to systemic findings and genotype.
Patients were systematically and prospectively examined at the National Institutes of Health (NIH) Clinical Center in the setting of a dedicated natural history clinical trial.
Ninety-nine patients with JS examined at a single center.
All patients underwent genotyping for JS, followed by complete age-appropriate ophthalmic examinations at the NIH Clinical Center, including visual acuity (VA), fixation behavior, lid position, motility assessment, slit-lamp biomicroscopy, dilated fundus examination with an indirect ophthalmoscope, and retinoscopy. Color and fundus autofluorescence imaging, Optos wide-field photography (Dunfermline, Scotland, UK), and electroretinography (ERG) were performed when possible.
The VA (with longitudinal follow-up where possible), ptosis, extraocular muscle function, retinal and optic nerve status, and retinal function as measured by ERG.
Among patients with JS with quantifiable VA (68/99), values ranged from 0 logarithm of the minimum angle of resolution (logMAR) (Snellen 20/20) to 1.5 logMAR (Snellen 20/632). Strabismus (71/98), nystagmus (66/99), oculomotor apraxia (60/77), ptosis (30/98), coloboma (28/99), retinal degeneration (20/83), and optic nerve atrophy (8/86) were identified.
We recommend regular monitoring for ophthalmological manifestations of JS beginning soon after birth or diagnosis. We demonstrate delayed visual development and note that the amblyogenic time frame may last significantly longer in JS than is typical. In general, patients with coloboma were less likely to display retinal degeneration, and those with retinal degeneration did not have coloboma. Severe retinal degeneration that is early and aggressive is seen in disease caused by specific genes, such as CEP290- and AHI1-associated JS. Retinal degeneration in INPP5E-, MKS1-, and NPHP1-associated JS was generally milder. Finally, ptosis surgery can be helpful in a subset of patients with JS; decisions as to timing and benefit/risk ratio need to be made on an individual basis according to expert consultation.
Abstract BACKGROUND This study investigated the potential of phosphorylated plasma Tau217 ratio (pTau217R) and plasma amyloid beta (Aβ) 42/Aβ40 in predicting brain amyloid levels measured by positron ...emission tomography (PET) Centiloid (CL) for Alzheimer's disease (AD) staging and screening. METHODS Quantification of plasma pTau217R and Aβ42/Aβ40 employed immunoprecipitation‐mass spectrometry. CL prediction models were developed on a cohort of 904 cognitively unimpaired, preclinical and early AD subjects and validated on two independent cohorts. RESULTS Models integrating pTau217R outperformed Aβ42/Aβ40 alone, predicting amyloid levels up to 89.1 CL. High area under the receiver operating characteristic curve (AUROC) values (89.3% to 94.7%) were observed across a broad CL range (15 to 90). Utilizing pTau217R‐based models for low amyloid levels reduced PET scans by 70.5% to 78.6%. DISCUSSION pTau217R effectively predicts brain amyloid levels, surpassing cerebrospinal fluid Aβ42/Aβ40's range. Combining it with plasma Aβ42/Aβ40 enhances sensitivity for low amyloid detection, reducing unnecessary PET scans and expanding clinical utility. Highlights Phosphorylated plasma Tau217 ratio (pTau217R) effectively predicts amyloid‐PET Centiloid (CL) across a broad spectrum. Integrating pTau217R with Aβ42/Aβ40 extends the CL prediction upper limit to 89.1 CL. Combined model predicts amyloid status with high accuracy, especially in cognitively unimpaired individuals. This model identifies subjects above or below various CL thresholds with high accuracy. pTau217R‐based models significantly reduce PET scans by up to 78.6% for screening out individuals with no/low amyloid.
Abundance-based model evaluations with observations
provide critical tests for the simulated mean state in models of
intercontinental pollution transport, and under certain conditions may also
offer ...constraints on model responses to emission changes. We compile
multiyear measurements of peroxy acetyl nitrate (PAN) available from five
mountaintop sites and apply them in a proof-of-concept approach that
exploits an ensemble of global chemical transport models (HTAP1) to identify
an observational “emergent constraint”. In April, when the signal from
anthropogenic emissions on PAN is strongest, simulated PAN at northern
midlatitude mountaintops correlates strongly with PAN source–receptor
relationships (the response to 20 % reductions in precursor emissions
within northern midlatitude continents; hereafter, SRRs). This finding
implies that PAN measurements can provide constraints on PAN SRRs by
limiting the SRR range to that spanned by the subset of models simulating
PAN within the observed range. In some cases, regional anthropogenic
volatile organic compound (AVOC) emissions, tracers of transport from
different source regions, and SRRs for ozone also correlate with PAN SRRs.
Given the large observed interannual variability in the limited available
datasets, establishing strong constraints will require matching meteorology
in the models to the PAN measurements. Application of this evaluation
approach to the chemistry–climate models used to project changes in
atmospheric composition will require routine, long-term mountaintop PAN
measurements to discern both the climatological SRR signal and its
interannual variability.
Progress in addressing the origins of intellectual and developmental disabilities accelerated with the establishment 50 years ago of the Eunice Kennedy Shriver National Institute of Child Health and ...Human Development of the National Institutes of Health and associated Intellectual and Developmental Disabilities Research Centers. Investigators at these Centers have made seminal contributions to understanding human brain and behavioral development and defining mechanisms and treatments of disorders of the developing brain. ANN NEUROL 2019;86:332–343
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