Toward a rational therapeutic for elastin related disease: Key considerations for elastin based regenerative medicine strategies.

Elastin is a connective tissue protein, produced from the ELN gene, that provides elasticity and recoil to tissues that stretch, such as the large arteries of the body, lung parenchyma, skin, ligaments and elastic cartilages. It is produced as a soluble monomer, tropoelastin, that when cross-linked in the extracellular space generates a polymer that is extraordinarily stable, with a predicted half-life of >70 years. Although data suggest ongoing elastin transcription, it is rare to see new elastin deposited outside of its tight developmental window.

Head and neck paraganglioma in Pacak-Zhuang syndrome.

Background: Head and neck paragangliomas (HNPGLs) are typically slow-growing, hormonally inactive tumors of parasympathetic paraganglia. Inactivation of prolyl-hydroxylase domain-containing 2 protein causing indirect gain-of-function of hypoxia-inducible factor-2α (HIF-2α), encoded by EPAS1, was recently shown to cause carotid body hyperplasia. We previously described a syndrome with multiple sympathetic paragangliomas caused by direct gain-of-function variants in EPAS1 (Pacak-Zhuang syndrome, PZS) and developed a corresponding mouse model.

Phenotypic findings associated with variation in elastin.

Variation in the elastin gene (ELN) may contribute to connective tissue disease beyond the known disease associations of supravalvar aortic stenosis and cutis laxa. Exome data from MyCode Community Health Initiative participants were analyzed for ELN rare variants (mean allele frequency <1%, not currently annotated as benign). Participants with variants of interest underwent phenotyping by dual chart review using a standardized abstraction tool.

Gastrointestinal manifestations in Williams syndrome: A prospective analysis of an adult and pediatric cohort.

Williams syndrome (WS) is a multi-system condition caused by the deletion of 25-27 coding genes on human chromosome 7. Irritability, gastrointestinal (GI) reflux and slow growth are commonly reported in infants with WS, but less data exist regarding GI concerns in older children and adults with the condition. This study evaluates 62 individuals with WS (31 children aged 3-17, and 31 adults aged 18-62) as well as 36 pediatric and adult controls to assess current and historical rates of common GI symptoms.

Increased heart rate fragmentation in those with Williams-Beuren syndrome suggests nonautonomic mechanistic contributors to sudden death risk.

Williams-Beuren syndrome (WBS) is a rare genetic condition caused by a chromosomal microdeletion at 7q11.23. It is a multisystem disorder characterized by distinct facies, intellectual disability, and supravalvar aortic stenosis (SVAS).

A comparative evaluation of ChatGPT 3.5 and ChatGPT 4 in responses to selected genetics questions.

Objectives: To evaluate the efficacy of ChatGPT 4 (GPT-4) in delivering genetic information about BRCA1, HFE, and MLH1, building on previous findings with ChatGPT 3.5 (GPT-3.5).

Genetic Testing for Supravalvar Aortic Stenosis: What to Do When It Is Not Williams Syndrome.

Background: We aimed to describe the frequency and yield of genetic testing in supravalvar aortic stenosis (SVAS) following negative evaluation for Williams-Beuren syndrome (WS).

Methods And Results: This retrospective cohort study included patients with SVAS at our institution who had a negative evaluation for WS from May 1991 to September 2021. SVAS was defined as (1) peak supravalvar velocity of ≥2 meters/second, (2) sinotubular junction or ascending aortic score <-2.

Matrisome and Immune Pathways Contribute to Extreme Vascular Outcomes in Williams-Beuren Syndrome.

Background: Supravalvar aortic stenosis (SVAS) is a characteristic feature of Williams-Beuren syndrome (WBS). Its severity varies: ~20% of people with Williams-Beuren syndrome have SVAS requiring surgical intervention, whereas ~35% have no appreciable SVAS. The remaining individuals have SVAS of intermediate severity.

Evaluating ChatGPT as an Agent for Providing Genetic Education.

Genetic disorders are complex and can greatly impact an individual's health and well-being. In this study, we assess the ability of ChatGPT, a language model developed by OpenAI, to answer questions related to three specific genetic disorders: BRCA1, MLH1, and HFE. ChatGPT has shown it can supply articulate answers to a wide spectrum of questions.

Age-related loss of Notch3 underlies brain vascular contractility deficiencies, glymphatic dysfunction, and neurodegeneration in mice.

Vascular aging affects multiple organ systems, including the brain, where it can lead to vascular dementia. However, a concrete understanding of how aging specifically affects the brain vasculature, along with molecular readouts, remains vastly incomplete. Here, we demonstrate that aging is associated with a marked decline in Notch3 signaling in both murine and human brain vessels.

Loss of Baz1b in mice causes perinatal lethality, growth failure, and variable multi-system outcomes.

BAZ1B is one of 25-27 coding genes deleted in canonical Williams syndrome, a multi-system disorder causing slow growth, vascular stenosis, and gastrointestinal complaints, including constipation. BAZ1B is involved in (among other processes) chromatin organization, DNA damage repair, and mitosis, suggesting reduced BAZ1B may contribute to Williams syndrome symptoms. In mice, loss of Baz1b causes early neonatal death.

A protocol for visualization of murine in situ neurovascular interfaces.

Mapping cranial vasculature and adjacent neurovascular interfaces in their entirety will enhance our understanding of central nervous system function in any physiologic state. We present a workflow to visualize in situ murine vasculature and surrounding cranial structures using terminal polymer casting of vessels, iterative sample processing and image acquisition, and automated image registration and processing. While this method does not obtain dynamic imaging due to mouse sacrifice, these studies can be performed before sacrifice and processed with other acquired images.

Heart Rate Variability Analysis May Identify Individuals With Williams-Beuren Syndrome at Risk of Sudden Death.

Background: Williams-Beuren syndrome (WBS) (Online Mendelian Inheritance in Man #194050) is a rare genetic multisystem disorder resulting from a chromosomal microdeletion at 7q11.23. The condition is characterized by distinct facies, intellectual disability, and supravalvar aortic stenosis.

NIH Toolbox Cognition Battery Feasibility in Individuals With Williams Syndrome.

The NIH Toolbox Cognition Battery (NIHTB-CB) was developed for epidemiological and longitudinal studies across a wide age span. Such a tool may be useful for intervention trials in conditions characterized by intellectual disability (ID), such as Williams syndrome (WS). Three NIHTB-CB tasks, including two executive functioning (Flanker, Dimensional Change Card Sort) and one episodic memory (Picture Sequence Memory) task, were given to 47 individuals with WS, ages 4 to 50, to evaluate feasibility (i.

Extending the spectrum in aortopathy: stenosis to aneurysm.

The size of the aorta varies in the healthy population and is influenced by a series of mostly common and lower-impact genomic variants. Rare, high-impact variants driving Mendelian diseases of stenosis and aneurysm extend the limits of aortic size out of the typical range. Pathology at both ends of the spectrum is governed by overlapping pathways and processes, such as those affecting structure, integrity, and function of the aorta.

Emerging mechanisms of elastin transcriptional regulation.

Elastin provides recoil to tissues that stretch such as the lung, blood vessels, and skin. It is deposited in a brief window starting in the prenatal period and extending to adolescence in vertebrates, and then slowly turns over. Elastin insufficiency is seen in conditions such as Williams-Beuren syndrome and elastin-related supravalvar aortic stenosis, which are associated with a range of vascular and connective tissue manifestations.

Novel ophthalmic findings and deep phenotyping in Williams-Beuren syndrome.

Background/aims: To characterise the ocular manifestations of Williams-Beuren syndrome (WBS) and compare these to patients with isolated elastin mediated supravalvular aortic stenosis (SVAS).

Methods: Fifty-seven patients with a diagnosis of WBS and five with SVAS underwent comprehensive ophthalmic evaluation at the National Institutes of Health from 2017 to 2020, including best-corrected visual acuity, slit-lamp biomicroscopy, optical biometry, dilated fundus examination, optical coherence tomography and colour fundus imaging.

Results: Mean age of the 57 WBS patients was 20.

Copper-Binding Domain Variation in a Novel Murine Lysyl Oxidase Model Produces Structurally Inferior Aortic Elastic Fibers Whose Failure Is Modified by Age, Sex, and Blood Pressure.

Lysyl oxidase (LOX) is a copper-binding enzyme that cross-links elastin and collagen. The dominant LOX variation contributes to familial thoracic aortic aneurysm. Previously reported murine Lox mutants had a mild phenotype and did not dilate without drug-induced provocation.

Airflow Obstruction in Adults with Williams Syndrome and Mice with Elastin Insufficiency.

Williams−Beuren syndrome (WS) results from the deletion of 25−27 coding genes, including elastin (ELN), on human chromosome 7q11.23. Elastin provides recoil to tissues; emphysema and chronic obstructive pulmonary disease have been linked to its destruction.

Elastin Insufficiency Confers Proximal and Distal Pulmonary Vasculopathy in Mice, Partially Remedied by the K Channel Opener Minoxidil: Considerations and Cautions for the Treatment of People With Williams-Beuren Syndrome.

Background: Williams Beuren syndrome (WBS) is a recurrent microdeletion disorder that removes one copy of elastin (), resulting in large artery vasculopathy. Early stenosis of the pulmonary vascular tree is common, but few data are available on longer-term implications of the condition.

Methods: Computed tomography (CT) angiogram ( = 11) and echocardiogram ( = 20) were performed in children with WBS aged 3.

Perspectives on Cognitive Phenotypes and Models of Vascular Disease.

Clinical investigations have established that vascular-associated medical conditions are significant risk factors for various kinds of dementia. And yet, we are unable to associate certain types of vascular deficiencies with specific cognitive impairments. The reasons for this are many, not the least of which are that most vascular disorders are multi-factorial and the development of vascular dementia in humans is often a multi-year or multi-decade progression.

Variegation of autism related traits across seven neurogenetic disorders.

Gene dosage disorders (GDDs) constitute a major class of genetic risks for psychopathology, but there is considerable debate regarding the extent to which different GDDs induce different psychopathology profiles. The current research speaks to this debate by compiling and analyzing dimensional measures of several autism-related traits (ARTs) across seven diverse GDDs. The sample included 350 individuals with one of 7 GDDs, as well as reference idiopathic autism spectrum disorder (ASD; n = 74) and typically developing control (TD; n = 171) groups.

Frequency of QTc Interval Prolongation in Children and Adults with Williams Syndrome.

QTc prolongation (≥ 460 ms), according to Bazett formula (QTcB), has been identified to be increased in Williams syndrome (WS) and suggested as a potential cause of increased risk of sudden cardiac death. The Bazett formula tends to overestimate QTc in higher heart rates. We performed a retrospective chart review of WS patients with ≥ 1 electrocardiogram (EKG) with sinus rhythm, no evidence of bundle branch blocks, and measurable intervals.

Loss of Angiotensin II Type 2 Receptor Improves Blood Pressure in Elastin Insufficiency.

There is ample evidence supporting a role for angiotensin II type 2 receptor (ATR) in counterbalancing the effects of angiotensin II (ang II) through the angiotensin II type 1 receptor by promoting vasodilation and having anti-inflammatory effects. Elastin insufficiency in both humans and mice results in large artery stiffness and systolic hypertension. Unexpectedly, mesenteric arteries from elastin insufficient ( ) mice were shown to have significant vasoconstriction to ATR agonism suggesting that ATR may have vasoconstrictor effects in elastin insufficiency.