The mammalian target of rapamycin (mTOR) and Akt proteins regulate various steps of muscle development and growth, but the physiological relevance and the downstream effectors are under ...investigation. Here we show that S6 kinase 1 (S6K1), a protein kinase activated by nutrients and insulin-like growth factors (IGFs), is essential for the control of muscle cytoplasmic volume by Akt and mTOR. Deletion of S6K1 does not affect myoblast cell proliferation but reduces myoblast size to the same extent as that observed with mTOR inhibition by rapamycin. In the differentiated state, S6K1−/− myotubes have a normal number of nuclei but are smaller, and their hypertrophic response to IGF1, nutrients and membrane-targeted Akt is blunted. These growth defects reveal that mTOR requires distinct effectors for the control of muscle cell cycle and size, potentially opening new avenues of therapeutic intervention against neoplasia or muscle atrophy.
The use of recorded video in medical education is increasing. Video material may be assigned before scheduled sessions to create a flipped classroom. Here, the instructor may lead a session that is ...organized for discussion, interpretation, and reflection of the previewed content. We established conditions that lead to increased student participation and engagement with prerecorded content for a medical genetics section in a first-year medical school basic sciences integrated course. Preliminary analysis of an asynchronous video-based pre-professional program directed the design of video material to support a first semester medical genetics course. We compared student participation in, and opinion of, a flipped-classroom session based on written vs. video presentation of material. Student opinion was surveyed with audience response devices (clickers). Shorter videos that were created specifically for the course were preferred by students compared to recordings of previously delivered lectures. Students preferred videos to assigned reading material and consistent scheduling throughout the teaching semester increased student participation. Presentation of medical school content with previously recorded video material can be a useful teaching tool if properly implemented.
The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we ...have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as “GENE-related phenotype descriptor” (e.g., “CFTR-related cystic fibrosis”). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships.
The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as “GENE-related phenotype descriptor” (e.g., “CFTR-related cystic fibrosis”). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships.
NALCN encodes a sodium ion leak channel expressed in the nervous system that conducts a persistent influx of sodium ions to facilitate action potential formation. Homozygous or compound heterozygous ...loss of function variants in NALCN cause infantile hypotonia with psychomotor retardation and characteristic facies‐1 (IHPRF1; OMIM 615419). Through exome and Sanger sequencing, we found two siblings of Afro‐Caribbean ancestry who are homozygous for a known NALCN pathogenic variant, p.Arg735Ter, leading to failure to thrive, severe hypotonia, and dolichocephaly. The older sibling died suddenly without a known etiology after evaluation but before molecular diagnosis. An international collaboration originating from a resource limited Caribbean island facilitated molecular diagnosis. Due to its small population, geographical isolation, and low socioeconomic status, the island lacks many specialty medical services, including clinical genetics. Descriptions of genetic disorders affecting individuals of Afro‐Caribbean ancestry are rarely reported in the medical literature. Diagnosis of IHPRF1 is important, as individuals with biallelic pathogenic NALCN variants are severely affected and potentially are at risk for cardiorespiratory arrest. Additionally, knowing the pathogenic variants allows the possibility of prenatal or preimplantation genetic diagnosis.
Summary
The Mpk1 MAP kinase of the Saccharomyces cerevisiae cell wall integrity signalling pathway phosphorylates and activates the Rlm1 transcription factor in response to cell wall stress. Rlm1 is ...related to mammalian MEF2 isoforms, and shares a similar DNA‐binding specificity. Signalling through Rlm1 regulates the expression of at least 25 genes, most of which have been implicated in cell wall biogenesis. We report here the transcriptional induction by agents of cell wall stress of a set of lacZ reporter plasmids derived from several Rlm1‐responsive genes. Analysis of substitution mutations at putative Mpk1 phosphorylation sites within Rlm1 revealed that Ser427 and Thr439 are important for its stress‐induced transcriptional activation of these reporter plasmids. Assessment of Rlm1 activation potency when fused to a heterologous DNA‐binding domain showed that the identified seryl and threonyl residues are necessary for the Rlm1 transcriptional activation function independently of its DNA binding. We also demonstrate that a MAP kinase docking site, shown recently to mediate activation of MEF2A and MEF2C, is conserved in Rlm1 and is required for its ability to mediate transcriptional activation in response to agents that induce cell wall stress. Finally, intracellular localization analyses show that Rlm1 resides in the nucleus regardless of its activation and phosphorylation status. Together these observations support the inference that Mpk1 regulates the Rlm1 transcriptional activation function by phosphorylation of Ser427 and Thr439.
Down syndrome in diverse populations Kruszka, Paul; Porras, Antonio R.; Sobering, Andrew K. ...
American journal of medical genetics. Part A,
January 2017, 2017-Jan, 2017-01-00, 20170101, Volume:
173, Issue:
1
Journal Article
Most of the geographically isolated island nations in the Caribbean have small populations and low gross national product. As such, many lack important medical and community services. Difficulties ...are compounded when attempting to care for children with special needs and genetic disorders such as Down syndrome. International charitable organizations can help to provide much needed specialty medical care. Community associations can encourage local relationship building and education. Collaborative efforts with well‐funded laboratories can help to deliver molecular characterization for individuals who have genetic disorders. With community and volunteer effort, a higher standard of care is obtainable in underserved communities.
Informing parents that their child has a diagnosis of Down syndrome (DS) is a common example of the delivery of unexpected or difficult news. Expectations and life planning will change, and if ...detected prenatally, discussions might include the option of pregnancy termination. Medical school curricula currently include training in breaking unexpected news; however, it is difficult to teach and assess. We use the perspectives of clinicians, educators, and a medical student who is the parent of a child with DS to frame a discussion on teaching, practicing, and assessing communication of difficult news in human genetics during medical school.
Pathogenic variants in ALG13 (ALG13 UDP‐N‐acetylglucosaminyltransferase subunit) cause an X‐linked congenital disorder of glycosylation (ALG13‐CDG) where individuals have variable clinical phenotypes ...that include developmental delay, intellectual disability, infantile spasms, and epileptic encephalopathy. Girls with a recurrent de novo c.3013C>T; p.(Asn107Ser) variant have normal transferrin glycosylation. Using a highly sensitive, semi‐quantitative flow injection‐electrospray ionization‐quadrupole time‐of‐flight mass spectrometry (ESI‐QTOF/MS) N‐glycan assay, we report subtle abnormalities in N‐glycans that normally account for <0.3% of the total plasma glycans that may increase up to 0.5% in females with the p.(Asn107Ser) variant. Among our 11 unrelated ALG13‐CDG individuals, one male had abnormal serum transferrin glycosylation. We describe seven previously unreported subjects including three novel variants in ALG13 and report a milder neurodevelopmental course. We also summarize the molecular, biochemical, and clinical data for the 53 previously reported ALG13‐CDG individuals. We provide evidence that ALG13 pathogenic variants may mildly alter N‐linked protein glycosylation in both female and male subjects, but the underlying mechanism remains unclear.
Hao-Fountain syndrome (HAFOUS) is a neurodevelopmental disorder caused by pathogenic variants in USP7. HAFOUS is characterized by developmental delay, intellectual disability, speech delay, ...behavioral abnormalities, autism spectrum disorder, seizures, hypogonadism, and mild dysmorphic features. We investigated the phenotype of 18 participants with HAFOUS and performed DNA methylation (DNAm) analysis, aiming to generate a diagnostic biomarker. Furthermore, we performed comparative analysis with known episignatures to gain more insight into the molecular pathophysiology of HAFOUS.
We assessed genomic DNAm profiles of 18 individuals with pathogenic variants and variants of uncertain significance (VUS) in USP7 to map and validate a specific episignature. The comparison between the USP7 cohort and 56 rare genetic disorders with earlier reported DNAm episignatures was performed with statistical and functional correlation.
We mapped a sensitive and specific DNAm episignature for pathogenic variants in USP7 and utilized this to reclassify the VUS. Comparative epigenomic analysis showed evidence of HAFOUS similarity to a number of other rare genetic episignature disorders.
We discovered a sensitive and specific DNAm episignature as a robust diagnostic biomarker for HAFOUS that enables VUS reclassification in USP7. We also expand the phenotypic spectrum of 9 new and 5 previously reported individuals with HAFOUS.
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