scholarly journals A deletion in CFL-2 gene associated with Severe Nemaline Myopathy with peculiar features

2021 ◽  
Author(s):  
Eduardo Macedo de Souza Tieppo ◽  
Miriam Eva Koch ◽  
Alzira Alves de Siqueira Carvalho
Keyword(s):  
Protein Trafficking ◽  
Nemaline Myopathy ◽  
Pubic Hair ◽  
Homozygous Deletion ◽  
Congenital Myopathy ◽  
Early Puberty ◽  
Sorting Nexin ◽  
New Variant ◽  
Severe Hypotonia ◽  
Previous Disease

Context: Nemaline myopathy (NM) is the most common congenital myopathy characterized by muscle weakness and presence of nemaline bodies (rods) in muscle biopsy. Phenotype ranges from neonatal death to normal lifespan. 13 genes have been reported. We describe a new variant in cofilin 2 gene (CFL2;OMIM*601443). Case report: A 5-year-old boy born severely hypotonic and unable to breathe, in need of mechanic ventilation. Healthy non-consanguineous parents. Physical examination: severe hypotonia with only extraocular motricity preserved and multiple contractures. Dysmorphic features were observed as brachycephaly, hypertelorism, pseudohypertrophy, macroglossia, premature pubic hair. Deep reflexes were absent. CK: 1010U/l. DHEA-S elevated. Muscular biopsy: Rods, cores and dystrophic pattern. Exome: homozygous deletion in exons 1 to 4 of CFL2 and partial deletion of the next gene Sorting nexin-6 (SNX6) in Chr14:34.563.122-34.714.639. Conclusion: 9 cases were described previously: Age onset was before 31 months. 4 presented respiratory distress at birth, 1 presented macroglossia, 2 contractures, 2 spinal deformities and 3 delayed motor milestones. Our patient presents an extent deletion in homozygosis not described before. A second deletion was found in SNX6, which is involved in protein trafficking and is expressed in different cells, as endocrine and cardiac. The early puberty and dimorphisms could be due to SNX6, though there is no previous disease caused by this gene. Among differential diagnosis of macroglossia, congenital myopathy caused by CFL2 should be considered.

scholarly journals Novel SNX13 Frameshift Variant in an Individual with Developmental Delay

2021 ◽  
pp. 1-6
Author(s):  
Xicheng Tao ◽  
Yueping Che ◽  
Chenxi Li ◽  
Wencong Ruan ◽  
Jialu Xu ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Protein Trafficking ◽  
Intracellular Signaling ◽  
Homozygous Deletion ◽  
Multiple Roles ◽  
Global Developmental Delay ◽  
Sorting Nexin ◽  
Cognitive Delay ◽  
Number Of Genes ◽  
First Time

Recently, an increasing number of genes have been associated with global developmental delay (GDD) and intellectual disability (ID). The sorting nexin (SNX) protein family plays multiple roles in protein trafficking and intracellular signaling. SNXs have been reported to be associated with several disorders, including Alzheimer disease and Down syndrome. Despite the growing evidence of an association of SNXs with neurodegeneration, SNX13 deficiency has not been associated with GDD or ID. In this study, we present the case of a 4-year-old boy with brain dysplasia and GDD, including language delay, cognitive delay, and dyskinesia. Exome sequencing revealed a 1-bp homozygous deletion in <i>SNX13</i> (NM_015132.5: exon8: c.742_743del; p.Tyr248Leufs*20), which caused a frameshift and predicted early termination. Sanger sequencing confirmed that the variant was inherited from his parents respectively. Our findings associate <i>SNX13</i> variation with GDD for the first time and provide a new GDD candidate gene.

scholarly journals A Role for Sorting Nexin 2 in Epidermal Growth Factor Receptor Down-regulation: Evidence for Distinct Functions of Sorting Nexin 1 and 2 in Protein Trafficking

2004 ◽  
Vol 15 (5) ◽  
pp. 2143-2155 ◽  
Author(s):  
Anuradha Gullapalli ◽  
Tiana A. Garrett ◽  
May M. Paing ◽  
Courtney T. Griffin ◽  
Yonghua Yang ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Protein Trafficking ◽  
Growth Factor Receptor ◽  
Down Regulation ◽  
Sorting Nexin ◽  
Px Domain ◽  
Early Endosomes ◽  
Epidermal Growth

Sorting nexin 1 (SNX1) and SNX2, homologues of the yeast vacuolar protein-sorting (Vps)5p, contain a phospholipid-binding motif termed the phox homology (PX) domain and a carboxyl terminal coiled-coil region. A role for SNX1 in trafficking of cell surface receptors from endosomes to lysosomes has been proposed; however, the function of SNX2 remains unknown. Toward understanding the function of SNX2, we first examined the distribution of endogenous protein in HeLa cells. We show that SNX2 resides primarily in early endosomes, whereas SNX1 is found partially in early endosomes and in tubulovesicular-like structures distributed throughout the cytoplasm. We also demonstrate that SNX1 interacts with the mammalian retromer complex through its amino terminal domain, whereas SNX2 does not. Moreover, activated endogenous epidermal growth factor receptor (EGFR) colocalizes markedly with SNX2-positive endosomes, but minimally with SNX1-containing vesicles. To assess SNX2 function, we examined the effect of a PX domain-mutated SNX2 that is defective in vesicle localization on EGFR trafficking. Mutant SNX2 markedly inhibited agonist-induced EGFR degradation, whereas internalization remained intact. In contrast, SNX1 PX domain mutants failed to effect EGFR degradation, whereas a SNX1 deletion mutant significantly inhibited receptor down-regulation. Interestingly, knockdown of SNX1 and SNX2 expression by RNA interference failed to alter agonist-induced EGFR down-regulation. Together, these findings suggest that both SNX1 and SNX2 are involved in regulating lysosomal sorting of internalized EGFR, but neither protein is essential for this process. These studies are the first to demonstrate a function for SNX2 in protein trafficking.

scholarly journals Fatal Nemaline Myopathy in Infancy

1984 ◽  
Vol 11 (2) ◽  
pp. 305-309 ◽  
Author(s):  
Joseph B. McMenamin ◽  
Bernadette Curry ◽  
Glen P. Taylor ◽  
Laurence E. Becker ◽  
E. Gordon Murphy
Keyword(s):  
Respiratory Failure ◽  
Peripheral Nerves ◽  
Neonatal Period ◽  
Nemaline Myopathy ◽  
Clinical Findings ◽  
Neural Basis ◽  
Limb Muscles ◽  
The Central Nervous System ◽  
Severe Hypotonia ◽  
Clinical Stability

ABSTRACT:The clinical and neuropathological findings in two infants with congenital nemaline myopathy are described. One patient presented at birth with severe hypotonia, respiratory failure and contractures and died shortly after the neonatal period. The other presented at age two months with hypotonia and, following a period of clinical stability, died at age seven months from respiratory failure. Pathological findings in the fatal neonatal case revealed numerous rod bodies in lingual, pharyngeal, diaphragm and limb muscles, correlating with clinical findings. Significant, but less rod body involvement was found in the diaphragm and limb muscles of the second patient. Although a neural basis has been suggested for this disorder, no abnormalities were found in the central nervous system or in the peripheral nerves of these two severely affected patients.

scholarly journals Heritability of Testosterone Levels in 12-Year-Old Twins and Its Relation to Pubertal Development

2006 ◽  
Vol 9 (4) ◽  
pp. 558-565 ◽  
Author(s):  
Rosa A. Hoekstra ◽  
Meike Bartels ◽  
Dorret I. Boomsma
Keyword(s):  
Pubertal Development ◽  
Environmental Influences ◽  
Pubic Hair ◽  
Self Report ◽  
Early Puberty ◽  
Salivary Testosterone ◽  
Testosterone Levels ◽  
Genital Development ◽  
Opposite Sex ◽  
Hair Development

AbstractThe aim of this study was to estimate the heritability of variation in testosterone levels in 12-year-old children, and to explore the overlap in genetic and environmental influences on circulating testosterone levels and androgen-dependent pubertal development. Midday salivary testosterone samples were collected on 2 consecutive days in a sample of 183 unselected twin pairs. Androgen-induced pubertal development was assessed using self-report Tanner scales of pubic hair development (boys and girls) and genital development (boys). A significant contribution of genetic effects to the variance in testosterone levels was found. Heritability was approximately 50% in both boys and girls. The remaining proportion of the variance in testosterone levels could be explained by nonshared environmental influences. The relatively high correlation between testosterone levels of opposite-sex dizygotic twins suggests that sex differences in genes influencing variation in testosterone levels have not yet developed in preand early puberty. Variance in pubertal development was explained by a large genetic component, moderate shared environmental influences, and a small nonshared environmental effect. Testosterone levels correlated moderately (r = .31) with pubertal development; the covariance between testosterone levels and pubertal development was entirely accounted for by genetic influences.

Precocious Puberty

2006 ◽  
Vol 00 (02) ◽  
Author(s):  
Paul B Kaplowitz
Keyword(s):  
Precocious Puberty ◽  
Linear Growth ◽  
Pubertal Development ◽  
Black Girls ◽  
Pubic Hair ◽  
Growth Spurt ◽  
Tall Stature ◽  
Early Puberty ◽  
Bone Maturation ◽  
Early Appearance

Precocious puberty refers to the appearance of physical and hormonal signs of pubertal development at an earlier age than is considered normal.Although traditionally, any signs of puberty in girls prior to age eight years have been considered abnormal, recent studies indicate that signs of early puberty (breasts and pubic hair) are often present in girls (particularly black girls) between ages 6–8 years.The early growth spurt initially can cause tall stature, but rapid bone maturation can cause linear growth to cease too early and result in short adult stature.The early appearance of breasts or menses in girls and increased libido in boys can cause emotional distress for some children.

scholarly journals The Role of Sorting Nexin 17 in Cardiac Development

2021 ◽  
Vol 8 ◽  
Author(s):  
Yufei Wu ◽  
Yaqun Zhou ◽  
Jian Huang ◽  
Ke Ma ◽  
Tianyou Yuan ◽  
...  
Keyword(s):  
Fetal Development ◽  
Messenger Rna ◽  
Cellular Proliferation ◽  
Cardiac Development ◽  
Heart Defects ◽  
Homozygous Deletion ◽  
Embryonic Lethality ◽  
Rat Tissues ◽  
Sorting Nexin

Sorting nexin 17 (SNX17), a member of sorting nexin (SNX) family, acts as a modulator for endocytic recycling of membrane proteins. Results from our previous study demonstrated the embryonic lethality of homozygous defect of SNX17. In this study, we investigated the role of SNX17 in rat fetal development. Specifically, we analyzed patterns of SNX17 messenger RNA (mRNA) expression in multiple rat tissues and found high expression in the cardiac outflow tract (OFT). This expression was gradually elevated during the cardiac OFT morphogenesis. Homozygous deletion of the SNX17 gene in rats resulted in mid-gestational embryonic lethality, which was accompanied by congenital heart defects, including the double-outlet right ventricle and atrioventricular and ventricular septal defects, whereas heterozygotes exhibited normal fetal development. Moreover, we found normal migration distance and the number of cardiac neural crest cells during the OFT morphogenesis. Although cellular proliferation in the cardiac OFT endocardial cushion was not affected, cellular apoptosis was significantly suppressed. Transcriptomic profiles and quantitative real-time PCR data in the cardiac OFT showed that SNX17 deletion resulted in abnormal expression of genes associated with cardiac development. Overall, these findings suggest that SNX17 plays a crucial role in cardiac development.

NEM6, KBTBD13-Related Congenital Myopathy: Myopathological Analysis in 18 Dutch Patients Reveals Ring Rods Fibers, Cores, Nuclear Clumps, and Granulo-Filamentous Protein Material

2021 ◽  
Vol 80 (4) ◽  
pp. 366-376
Author(s):  
Karlijn Bouman ◽  
Benno Küsters ◽  
Josine M De Winter ◽  
Cynthia Gillet ◽  
Esmee S B Van Kleef ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Light Microscopy ◽  
Clinical Phenotype ◽  
Fiber Type ◽  
Muscle Relaxation ◽  
Nemaline Myopathy ◽  
Congenital Myopathy ◽  
Thin Filaments ◽  
Core Myopathy

AbstractNemaline myopathy type 6 (NEM6), KBTBD13-related congenital myopathy is caused by mutated KBTBD13 protein that interacts improperly with thin filaments/actin, provoking impaired muscle-relaxation kinetics. We describe muscle morphology in 18 Dutch NEM6 patients and correlate it with clinical phenotype and pathophysiological mechanisms. Rods were found in in 85% of biopsies by light microscopy, and 89% by electron microscopy. A peculiar ring disposition of rods resulting in ring-rods fiber was observed. Cores were found in 79% of NEM6 biopsies by light microscopy, and 83% by electron microscopy. Electron microscopy also disclosed granulofilamentous protein material in 9 biopsies. Fiber type 1 predominance and prominent nuclear internalization were found. Rods were immunoreactive for α-actinin and myotilin. Areas surrounding the rods showed titin overexpression suggesting derangement of the surrounding sarcomeres. NEM6 myopathology hallmarks are prominent cores, rods including ring-rods fibers, nuclear clumps, and granulofilamentous protein material. This material might represent the histopathologic epiphenomenon of altered interaction between mutated KBTBD13 protein and thin filaments. We claim to classify KBTBD13-related congenital myopathy as rod-core myopathy.

scholarly journals Gibberellin DELLA signaling targets the retromer complex to redirect protein trafficking to the plasma membrane

2018 ◽  
Vol 115 (14) ◽  
pp. 3716-3721 ◽  
Author(s):  
Yuliya Salanenka ◽  
Inge Verstraeten ◽  
Christian Löfke ◽  
Kaori Tabata ◽  
Satoshi Naramoto ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cell Surface ◽  
Protein Trafficking ◽  
Molecular Mechanisms ◽  
Sorting Nexin ◽  
Protein Traffic ◽  
Della Proteins ◽  
Retromer Complex ◽  
Ga Signaling ◽  
Multiple Processes

The plant hormone gibberellic acid (GA) is a crucial regulator of growth and development. The main paradigm of GA signaling puts forward transcriptional regulation via the degradation of DELLA transcriptional repressors. GA has also been shown to regulate tropic responses by modulation of the plasma membrane incidence of PIN auxin transporters by an unclear mechanism. Here we uncovered the cellular and molecular mechanisms by which GA redirects protein trafficking and thus regulates cell surface functionality. Photoconvertible reporters revealed that GA balances the protein traffic between the vacuole degradation route and recycling back to the cell surface. Low GA levels promote vacuolar delivery and degradation of multiple cargos, including PIN proteins, whereas high GA levels promote their recycling to the plasma membrane. This GA effect requires components of the retromer complex, such as Sorting Nexin 1 (SNX1) and its interacting, microtubule (MT)-associated protein, the Cytoplasmic Linker-Associated Protein (CLASP1). Accordingly, GA regulates the subcellular distribution of SNX1 and CLASP1, and the intact MT cytoskeleton is essential for the GA effect on trafficking. This GA cellular action occurs through DELLA proteins that regulate the MT and retromer presumably via their interaction partners Prefoldins (PFDs). Our study identified a branching of the GA signaling pathway at the level of DELLA proteins, which, in parallel to regulating transcription, also target by a nontranscriptional mechanism the retromer complex acting at the intersection of the degradation and recycling trafficking routes. By this mechanism, GA can redirect receptors and transporters to the cell surface, thus coregulating multiple processes, including PIN-dependent auxin fluxes during tropic responses.

scholarly journals Early life household intactness and timing of pubertal onset in girls: a prospective cohort study

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Sara Aghaee ◽  
Julianna Deardorff ◽  
Louise C. Greenspan ◽  
Charles P. Quesenberry ◽  
Lawrence H. Kushi ◽  
...  
Keyword(s):  
Cohort Study ◽  
Prospective Cohort Study ◽  
Prospective Cohort ◽  
Early Life ◽  
Pubertal Development ◽  
Pubic Hair ◽  
Interval Censoring ◽  
Early Puberty ◽  
Pubertal Onset ◽  
Increased Risk

Abstract Background Girls who experience early-life familial stress may have heightened risk of early puberty, which has adverse implications for adolescent and adult health. We assessed the association between household intactness and pubertal onset using a racially/ethnically diverse cohort of girls from Northern California. Methods A prospective cohort study of 26,044 girls born in 2003-10. Girls living with both parents from birth up to 6 years were considered to come from “intact” households while others constituted “non-intact” households. Pubertal development was measured using pediatrician-assessed Tanner staging for breast and pubic hair. Pubertal onset was defined as the transition from Tanner Stage 1 to 2+ for breast (thelarche) and pubic hair (pubarche). Menarche data was collected from routine well-child questionnaires. Weibull regression models accommodating left, right, and interval censoring were used to determine risk of earlier thelarche and pubarche, and logistic regressions were used to assess the risk of early menarche (age < 12). Results Girls exposed to non-intact households before age 2 years were at increased risk for earlier thelarche and pubarche with significant effect modification by race/ethnicity, compared with girls from intact households. The associations were strongest among Black girls (adjusted hazard ratio [HR]: 1.60, 95% confidence interval [CI]: 1.29,1.98; HR: 1.42, 95%CI: 1.15,1.77 for thelarche and pubarche, respectively). There were no significant associations among Asian/Pacific Islanders. Girls who lived in non-intact households before age 2 years were also at increased risk for earlier menarche, but without race/ethnic interaction. Adjustment for prepubertal obesity did not change these associations. Associations between living in non-intact households after age 2 years and early puberty were weaker but still significant. Conclusions Exposure to a non-intact household early in life may increase the risk of early puberty in girls. Future psychosocial interventions focused on improving family cohesiveness and efforts to reduce childhood stress among families that are non-intact may mitigate these negative associations, thereby preventing future adverse health effects of early puberty and health disparities.

scholarly journals l-Carnitine ameliorates congenital myopathy in a tropomyosin 3 de novo mutation transgenic zebrafish

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Po-Jui Hsu ◽  
Horng-Dar Wang ◽  
Yung-Che Tseng ◽  
Shao-Wei Pan ◽  
Bonifasius Putera Sampurna ◽  
...  
Keyword(s):  
Expression Profiling ◽  
De Novo ◽  
Fiber Type ◽  
Transgenic Fish ◽  
Nemaline Myopathy ◽  
Histochemical Staining ◽  
Congenital Myopathy ◽  
De Novo Mutation ◽  
Muscle Endurance ◽  
Transgenic Zebrafish

Abstract Background Congenital myopathy (CM) is a group of clinically and genetically heterogeneous muscle disorders, characterized by muscle weakness and hypotonia from birth. Currently, no definite treatment exists for CM. A de novo mutation in Tropomyosin 3-TPM3(E151G) was identified from a boy diagnosed with CM, previously TPM3(E151A) was reported to cause CM. However, the role of TPM3(E151G) in CM is unknown. Methods Histopathological, swimming behavior, and muscle endurance were monitored in TPM3 wild-type and mutant transgenic fish, modelling CM. Gene expression profiling of muscle of the transgenic fish were studied through RNAseq, and mitochondria respiration was investigated. Results While TPM3(WT) and TPM3(E151A) fish show normal appearance, amazingly a few TPM3(E151G) fish display either no tail, a crooked body in both F0 and F1 adults. Using histochemical staining for the muscle biopsy, we found TPM3(E151G) displays congenital fiber type disproportion and TPM3(E151A) resembles nemaline myopathy. TPM3(E151G) transgenic fish dramatically swimming slower than those in TPM3(WT) and TPM3(E151A) fish measured by DanioVision and T-maze, and exhibit weaker muscle endurance by swimming tunnel instrument. Interestingly, l-carnitine treatment on TPM3(E151G) transgenic larvae significantly improves the muscle endurance by restoring the basal respiration and ATP levels in mitochondria. With RNAseq transcriptomic analysis of the expression profiling from the muscle specimens, it surprisingly discloses large downregulation of genes involved in pathways of sodium, potassium, and calcium channels, which can be rescued by l-carnitine treatment, fatty acid metabolism was differentially dysregulated in TPM3(E151G) fish and rescued by l-carnitine treatment. Conclusions These results demonstrate that TPM3(E151G) and TPM3(E151A) exhibit different pathogenicity, also have distinct gene regulatory profiles but the ion channels were downregulated in both mutants, and provides a potential mechanism of action of TPM3 pathophysiology. Our results shed a new light in the future development of potential treatment for TPM3-related CM.

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