BCS1L-Associated Disease: 5'-UTR Variant Shifts the Phenotype Towards Axonal Neuropathy.

Objectives: To investigate the consequences of a pathogenic missense variant (c.838C>T; p.L280F) and a 5'-UTR regulatory variant (c.

Collagen type VI regulates TGF-β bioavailability in skeletal muscle in mice.

Collagen VI-related disorders (COL6-RDs) are a group of rare muscular dystrophies caused by pathogenic variants in collagen VI genes (COL6A1, COL6A2, and COL6A3). Collagen type VI is a heterotrimeric, microfibrillar component of the muscle extracellular matrix (ECM), predominantly secreted by resident fibroadipogenic precursor cells in skeletal muscle. The absence or mislocalization of collagen VI in the ECM underlies the noncell-autonomous dysfunction and dystrophic changes in skeletal muscle with a yet elusive direct mechanistic link between the ECM and myofiber dysfunction.

RNA sequencing driven diagnosis expands the phenotypic spectrum of NBAS deficiency.

One in 10 individuals has a rare disease, with exome and genome sequencing yielding an overall diagnostic rate of approximately 30 %. RNA sequencing can augment genome analysis and improve diagnosis. We present a young woman with global developmental delay, poor growth, distinctive facial features, osteopenia, premature ovarian insufficiency, and ocular abnormalities who had non-diagnostic genome sequencing.

Mitochondrial trifunctional protein deficiency caused by a deep intronic deletion leading to aberrant splicing.

Trifunctional protein deficiency (TFP) is a disorder of fatty acid beta-oxidation associated with metabolic, cardiac, and liver dysfunction in severe forms. We present two siblings diagnosed by newborn screening and confirmed by biochemical testing at birth. Their clinical course was complicated by recurrent rhabdomyolysis, retinopathy, and hypoparathyroidism.

Differential inclusion of NEB exons 143 and 144 provides insight into NEB-related myopathy variant interpretation and disease manifestation.

Biallelic pathogenic variants in the gene encoding nebulin (NEB) are a known cause of congenital myopathy. We present two brothers with congenital myopathy and compound heterozygous variants (NC_000002.12:g.

CIAO1 loss of function causes a neuromuscular disorder with compromise of nucleocytoplasmic Fe-S enzymes.

Cytoplasmic and nuclear iron-sulfur (Fe-S) enzymes that are essential for genome maintenance and replication depend on the cytoplasmic Fe-S assembly (CIA) machinery for cluster acquisition. The core of the CIA machinery consists of a complex of CIAO1, MMS19 and FAM96B. The physiological consequences of loss of function in the components of the CIA pathway have thus far remained uncharacterized.

Collagen type VI regulates TGFβ bioavailability in skeletal muscle.

Collagen VI-related disorders (-RDs) are a group of rare muscular dystrophies caused by pathogenic variants in collagen VI genes (, and ). Collagen type VI is a heterotrimeric, microfibrillar component of the muscle extracellular matrix (ECM), predominantly secreted by resident fibroadipogenic precursor cells in skeletal muscle. The absence or mislocalizatoion of collagen VI in the ECM underlies the non-cell autonomous dysfunction and dystrophic changes in skeletal muscle with an as of yet elusive direct mechanistic link between the ECM and myofiber dysfunction.

A humanized knock-in mouse recapitulates a deep-intronic splice-activating variant.

Antisense therapeutics such as splice-modulating antisense oligonucleotides (ASOs) are promising tools to treat diseases caused by splice-altering intronic variants. However, their testing in animal models is hampered by the generally poor sequence conservation of the intervening sequences between human and other species. Here we aimed to model in the mouse a recurrent, deep-intronic, splice-activating, variant, associated with a severe form of Collagen VI-related muscular dystrophies (COL6-RDs), for the purpose of testing human-ready antisense therapeutics .

Differential inclusion of exons 143 and 144 provides insight into -related myopathy variant interpretation and disease manifestation.

Biallelic pathogenic variants in the gene encoding nebulin () are a known cause of congenital myopathy. We present two individuals with congenital myopathy and compound heterozygous variants (NM_001271208.2: c.

Clinical, immunohistochemical, and genetic characterization of splice-altering biallelic DES variants: Therapeutic implications.

Pathogenic variants in the DES gene clinically manifest as progressive skeletal muscle weakness, cardiomyopathy with associated severe arrhythmias, and respiratory insufficiency, and are collectively known as desminopathies. While most DES pathogenic variants act via a dominant mechanism, recessively acting variants have also been reported. Currently, there are no effective therapeutic interventions for desminopathies of any type.

Stress and coping strategies in pediatric dental residents.

Purpose/objectives: This study examines the amount and sources of stress, as well as coping strategies, exercise, and alcohol use, among pediatric dental residents in the United States.

Methods: One hundred fifty pediatric dental residents (n = 76 postgraduate year [PGY] 1; n = 74 PGY2) in 2-year residency programs responded to an anonymous survey that included demographic questions, the Perceived Stress Scale (PSS), Graduate Dental Environment Stress Scale (GDES), Tactics For Coping With Stress Inventory, and questions about alcohol consumption and exercise.

Results: Stress scores were moderate (mean PSS = 16.

A novel intronic homozygous mutation in the AMT gene of a patient with nonketotic hyperglycinemia and hyperammonemia.

Nonketotic Hyperglycinemia is an autosomal recessive disorder characterized by defects in the mitochondrial glycine cleavage system. Most patients present soon after birth with seizures and hypotonia, and infants that survive the newborn period often have profound intellectual disability and intractable seizures. Here we present a case report of a 4-year-old girl with NKH as well as hyperammonemia, an uncommon finding in NKH.

α2* Nicotinic acetylcholine receptors influence hippocampus-dependent learning and memory in adolescent mice.

The absence of α2* nicotinic acetylcholine receptors (nAChRs) in oriens lacunosum moleculare (OLM) GABAergic interneurons ablate the facilitation of nicotine-induced hippocampal CA1 long-term potentiation and impair memory. The current study delineated whether genetic mutations of α2* nAChRs ( and ) influence hippocampus-dependent learning and memory and CA1 synaptic plasticity. We substituted a serine for a leucine (L9'S) in the α2 subunit (encoded by the gene) to make a hypersensitive nAChR.

A longitudinal study of stress in first-year dental students.

This study examines the association of stress with performance and health in first-year dental students and changes in the amount and sources of stress over one year. Students at four U.S.

The effect of condyle fossa relationships on head posture.

Although it is commonly accepted that there is an interrelationship between the temporomandibular joint (TMJ) and head posture, few, if any, previous studies have quantified this effect. The purpose of this study is to quantify the effect of a change in the condyle fossa relationship of symptomatic temporomandibular joints on head posture. Charts of 51 patients (N=10 men and N=41 women) with symptomatic TMJ pathology were reviewed.