scholarly journals Hyperkinetic stereotyped movements in a boy with biallelic CNTNAP2 variants

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Marcello Scala ◽  
Midas Anijs ◽  
Roberta Battini ◽  
Francesca Madia ◽  
Valeria Capra ◽  
...  
Keyword(s):  
Missense Variant ◽  
Clinical Feature ◽  
Comparative Genomic ◽  
Speech Impairment ◽  
Coding Region ◽  
Exon 2 ◽  
Genetic Syndrome ◽  
Abnormal Movements ◽  
Intron 1 ◽  
Wide Range

Abstract Background Heterozygous variants in CNTNAP2 have been implicated in a wide range of neurological phenotypes, including intellectual disability (ID), epilepsy, autistic spectrum disorder (ASD), and impaired language. However, heterozygous variants can also be found in unaffected individuals. Biallelic CNTNAP2 variants are rarer and cause a well-defined genetic syndrome known as CASPR2 deficiency disorder, a condition characterised by ID, early-onset refractory epilepsy, language impairment, and autistic features. Case-report A 7-year-old boy presented with hyperkinetic stereotyped movements that started during early infancy and persisted over childhood. Abnormal movements consisted of rhythmic and repetitive shaking of the four limbs, with evident stereotypic features. Additional clinical features included ID, attention deficit-hyperactivity disorder (ADHD), ASD, and speech impairment, consistent with CASPR2 deficiency disorder. Whole-genome array comparative genomic hybridization detected a maternally inherited 0.402 Mb duplication, which involved intron 1, exon 2, and intron 2 of CNTNAP2 (c.97 +?_209-?dup). The affected region in intron 1 contains a binding site for the transcription factor FOXP2, potentially leading to abnormal CNTNAP2 expression regulation. Sanger sequencing of the coding region of CNTNAP2 also identified a paternally-inherited missense variant c.2752C > T, p.(Leu918Phe). Conclusion This case expands the molecular and phenotypic spectrum of CASPR2 deficiency disorder, suggesting that Hyperkinetic stereotyped movements may be a rare, yet significant, clinical feature of this complex neurological disorder. Furthermore, the identification of an in-frame, largely non-coding duplication in CNTNAP2 points to a sophisticated underlying molecular mechanism, likely involving impaired FOXP2 binding.

scholarly journals The E7 Oncoprotein Is Translated from Spliced E6*I Transcripts in High-Risk Human Papillomavirus Type 16- or Type 18-Positive Cervical Cancer Cell Lines via Translation Reinitiation

2006 ◽  
Vol 80 (9) ◽  
pp. 4249-4263 ◽  
Author(s):  
Shuang Tang ◽  
Mingfang Tao ◽  
J. Philip McCoy ◽  
Zhi-Ming Zheng
Keyword(s):  
Cervical Cancer ◽  
High Risk ◽  
Cell Lines ◽  
Rna Splicing ◽  
Human Papillomaviruses ◽  
Small Interfering Rnas ◽  
Coding Region ◽  
Exon 2 ◽  
E7 Oncoprotein ◽  
Intron 1

ABSTRACT High-risk human papillomaviruses (HPVs) encode two viral oncoproteins, E6 and E7, from a single bicistronic pre-mRNA containing three exons and two introns. Retention of intron 1 in the E6 coding region is essential for production of the full-length E6 oncoprotein. However, splicing of intron 1 is extremely efficient in cervical cancer cells, leading to the production of a spliced transcript, E6*I, of E6. Here, we investigated whether this splicing of intron 1 might benefit E7 production. Using RNA interference as a tool, we targeted the intron 1 region using small interfering RNAs (siRNAs) in HPV-positive cell lines. At an effective low dose, the siRNAs specifically suppressed E6 expression but not E7 expression, as demonstrated by the stabilization of p53. However, at high doses the HPV18 intron 1-specific siRNA substantially and specifically reduced the level of the 18E6*I mRNA lacking the intron region in HeLa cells, implying its nuclear silencing on the pre-mRNA before RNA splicing. Two other siRNAs targeting the exon 2 regions of HPV16 and -18, which encode the E7 oncoprotein, reduced the E6*I mRNAs to a remarkable extent and preferentially suppressed expression of E7, leading to accumulation of hypophosphorylated p105Rb and cell cycle arrest, indicating that the majority of E7 proteins are the translational products of E6*I mRNAs. This was confirmed by transient transfection in 293 cells: E7 could be translated only from the E7 open reading frame (ORF) on E6*I mRNA in a distance-dependent matter of upstream E6*I ORF by translation reinitiation. The data thus provide direct evidence that the E6*I mRNAs of high-risk HPVs are responsible for E7 production.

scholarly journals Lack of mutations in the leptin receptor gene in severely obese children

2012 ◽  
Vol 56 (3) ◽  
pp. 178-183 ◽  
Author(s):  
Natasha Favoretto Dias ◽  
Ariana Ester Fernandes ◽  
Maria Edna de Melo ◽  
Heidi Lui Reinhardt ◽  
Cintia Cercato ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Receptor Gene ◽  
Hdl Cholesterol ◽  
Molecular Study ◽  
Serum Glucose ◽  
Clinical Feature ◽  
Coding Region ◽  
Obese Children ◽  
Exon 2 ◽  
Low Hdl

OBJECTIVE: To analyze the LEPR gene in obese children and to investigate the associations between molecular findings and anthropometric and metabolic features. SUBJECTS AND METHODS: Thirty-two patients were evaluated regarding anthropometric characteristics, blood pressure, heart rate, serum glucose, insulin, leptin levels, and lipid profile. The molecular study consisted of the amplification and automatic sequencing of the coding region of LEPR in order to investigate new mutations. RESULTS: We identified a high prevalence of metabolic disorders: impaired fasting glucose in 12.5% of the patients, elevated HOMA-IR in 85.7%, low HDL-cholesterol levels in 46.9%, high triglyceride levels in 40.6%, and hypertension in 58.6% of the patients. The molecular study identified 6 already described allelic variants: rs1137100 (exon-2), rs1137101 (exon-4), rs1805134 (exon-7), rs8179183 (exon-12), rs1805096 (exon-18), and the deletion/insertion of the pentanucleotide CTTTA at 3'untranslated region. CONCLUSIONS: The frequency of alleles observed in this cohort is similar to that described in the literature, and was not correlated with any clinical feature. The molecular findings in the analysis of the LEPR did not seem to be implicated in the etiology of obesity in these patients.

scholarly journals Mitogenomics and Evolutionary History of Rodent Whipworms (Trichuris spp.) Originating from Three Biogeographic Regions

Life ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 540
Author(s):  
Jan Petružela ◽  
Alexis Ribas ◽  
Joëlle Goüy de Bellocq
Keyword(s):  
Phylogenetic Analyses ◽  
Eastern Africa ◽  
Comparative Genomic ◽  
Trna Genes ◽  
Whole Genome ◽  
Coding Region ◽  
Trichuris Muris ◽  
Protein Coding ◽  
Wide Range ◽  
Biogeographic Regions

Trichuris spp. is a widespread nematode which parasitizes a wide range of mammalian hosts including rodents, the most diverse mammalian order. However, genetic data on rodent whipworms are still scarce, with only one published whole genome (Trichuris muris) despite an increasing demand for whole genome data. We sequenced the whipworm mitogenomes from seven rodent hosts belonging to three biogeographic regions (Palearctic, Afrotropical, and Indomalayan), including three previously described species: Trichuris cossoni, Trichurisarvicolae, and Trichurismastomysi. We assembled and annotated two complete and five almost complete mitogenomes (lacking only the long non-coding region) and performed comparative genomic and phylogenetic analyses. All the mitogenomes are circular, have the same organisation, and consist of 13 protein-coding, 2 rRNA, and 22 tRNA genes. The phylogenetic analysis supports geographical clustering of whipworm species and indicates that T. mastomysi found in Eastern Africa is able to infect multiple closely related rodent hosts. Our results are informative for species delimitation based on mitochondrial markers and could be further used in studies on phylogeny, phylogeography, and population genetics of rodent whipworms

scholarly journals 5′ Region Large Genomic Rearrangements in the BRCA1 Gene in French Families: Identification of a Tandem Triplication and Nine Distinct Deletions with Five Recurrent Breakpoints

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3171
Author(s):  
Sandrine M. Caputo ◽  
Dominique Telly ◽  
Adrien Briaux ◽  
Julie Sesen ◽  
Maurizio Ceppi ◽  
...  
Keyword(s):  
Brca1 Gene ◽  
Genomic Rearrangements ◽  
Comparative Genomic ◽  
Homologous Region ◽  
Exon 2 ◽  
Large Genomic Rearrangements ◽  
Causality Score ◽  
Frequent Site ◽  
First Time ◽  
Intron 2

Background: Large genomic rearrangements (LGR) in BRCA1 consisting of deletions/duplications of one or several exons have been found throughout the gene with a large proportion occurring in the 5′ region from the promoter to exon 2. The aim of this study was to better characterize those LGR in French high-risk breast/ovarian cancer families. Methods: DNA from 20 families with one apparent duplication and nine deletions was analyzed with a dedicated comparative genomic hybridization (CGH) array, high-resolution BRCA1 Genomic Morse Codes analysis and Sanger sequencing. Results: The apparent duplication was in fact a tandem triplication of exons 1 and 2 and part of intron 2 of BRCA1, fully characterized here for the first time. We calculated a causality score with the multifactorial model from data obtained from six families, classifying this variant as benign. Among the nine deletions detected in this region, eight have never been identified. The breakpoints fell in six recurrent regions and could confirm some specific conformation of the chromatin. Conclusions: Taken together, our results firmly establish that the BRCA1 5′ region is a frequent site of different LGRs and highlight the importance of the segmental duplication and Alu sequences, particularly the very high homologous region, in the mechanism of a recombination event. This also confirmed that those events are not systematically deleterious.

scholarly journals Cortical Excitability across the ALS Clinical Motor Phenotypes

2021 ◽  
Vol 11 (6) ◽  
pp. 715
Author(s):  
Thanuja Dharmadasa
Keyword(s):  
Motor Cortex ◽  
Cortical Excitability ◽  
Phenotypic Variability ◽  
Specific Treatment ◽  
Underlying Disease ◽  
Selective Vulnerability ◽  
Clinical Feature ◽  
Cortical Hyperexcitability ◽  
Wide Range

Amyotrophic lateral sclerosis (ALS) is characterized by its marked clinical heterogeneity. Although the coexistence of upper and lower motor neuron signs is a common clinical feature for most patients, there is a wide range of atypical motor presentations and clinical trajectories, implying a heterogeneity of underlying pathogenic mechanisms. Corticomotoneuronal dysfunction is increasingly postulated as the harbinger of clinical disease, and neurophysiological exploration of the motor cortex in vivo using transcranial magnetic stimulation (TMS) has suggested that motor cortical hyperexcitability may be a critical pathogenic factor linked to clinical features and survival. Region-specific selective vulnerability at the level of the motor cortex may drive the observed differences of clinical presentation across the ALS motor phenotypes, and thus, further understanding of phenotypic variability in relation to cortical dysfunction may serve as an important guide to underlying disease mechanisms. This review article analyses the cortical excitability profiles across the clinical motor phenotypes, as assessed using TMS, and explores this relationship to clinical patterns and survival. This understanding will remain essential to unravelling central disease pathophysiology and for the development of specific treatment targets across the ALS clinical motor phenotypes.

scholarly journals Assessing evidence for adaptive evolution in two hearing-related genes important for high-frequency hearing in echolocating mammals

2021 ◽  
Author(s):  
Hui Wang ◽  
Hanbo Zhao ◽  
Yujia Chu ◽  
Jiang Feng ◽  
Keping Sun
Keyword(s):  
Adaptive Evolution ◽  
Hair Cells ◽  
High Frequency ◽  
Phylogenetic Trees ◽  
Outer Hair Cells ◽  
Functional Domain ◽  
Coding Region ◽  
Selective Pressures ◽  
Wide Range ◽  
Different Parts

Abstract High-frequency hearing is particularly important for echolocating bats and toothed whales. Previously, studies of the hearing-related genes Prestin, KCNQ4, and TMC1 documented that adaptive evolution of high-frequency hearing has taken place in echolocating bats and toothed whales. In this study, we present two additional candidate hearing-related genes, Shh and SK2, that may also have contributed to the evolution of echolocation in mammals. Shh is a member of the vertebrate Hedgehog gene family and is required in the specification of the mammalian cochlea. SK2 is expressed in both inner and outer hair cells, and it plays an important role in the auditory system. The coding region sequences of Shh and SK2 were obtained from a wide range of mammals with and without echolocating ability. The topologies of phylogenetic trees constructed using Shh and SK2 were different; however, multiple molecular evolutionary analyses showed that those two genes experienced different selective pressures in echolocating bats and toothed whales compared to non-echolocating mammals. In addition, several nominally significant positively selected sites were detected in the non-functional domain of the SK2 gene, indicating that different selective pressures were acting on different parts of the SK2 gene. This study has expanded our knowledge of the adaptive evolution of high-frequency hearing in echolocating mammals.

El gen del receptor CCK-A posiblemente está asociado con las alucinaciones auditivas en la esquizofrenia

1999 ◽  
Vol 6 (7) ◽  
pp. 428-432
Author(s):  
J. Wei ◽  
G.P. Hemmings
Keyword(s):  
Exon 2 ◽  
Intron 1

ResumenEn este estudio, se identificó un locus polimórfico de Pstl con dos alelos individuales, a saber, Al y A2, dentro del límite entre el intrón 1 y el exón 2 del gen del receptor tipo A de la colecistoquini-na (CCK). El locus polimórfico de Pstl se utilizó como marcador genético para estudiar su asociación con síntomas psicóticos en la esquizofrenia. Se encontró una diferencia significativa en la frecuencia alélica entre los pacientes esquizofrénicos con y sin alucinaciones auditivas (χ2 = 6,26, gl = 1, P = 0,012), y la relación de ventaja para la asociación alélica fue 2,21 (IC de 95% = 1,18-4,15), con una fracción atribuible de 0,1. La frecuencia de los genotipos A1-A1 y A1-A2 mostró una presencia mayor significativa en los pacientes esquizofrénicos con alucinaciones auditivas en comparación con los pacientes sin estos síntomas (χ2 = 5,45, gl = 1, P = 0,02), y la relación de ventaja para la asociación genotípica fue 2,27 (IC de 95% = 1,13-4,57), con una fracción atribuible de 0,177. La prueba de riesgo relativo de haplotipo basada en el haplotipo (HHRR) reveló una diferencia significativa entre los alelos transmitidos y no transmitidos en las familias nucleares de los pacientes esquizofrénicos con alucinaciones auditivas (χ2 = 4,54, gl = 1, P = 0,033), pero no en las familias de los pacientes esquizofrénicos sin ellas. El presente estudio indica que el gen del receptor CCK-A puede estar asociado con las alucinaciones auditivas en la esquizofrenia.

scholarly journals Complete Thyroxine-Binding Globulin (TBG) Deficiency Produced by a Mutation in Acceptor Splice Site Causing Frameshift and Early Termination of Translation (TBG-Kankakee)12

1998 ◽  
Vol 83 (10) ◽  
pp. 3604-3608
Author(s):  
Gisah A. Carvalho ◽  
Roy E. Weiss ◽  
Samuel Refetoff
Keyword(s):  
Splice Site ◽  
Messenger Rna ◽  
Restriction Site ◽  
Splice Junction ◽  
Early Termination ◽  
Coding Region ◽  
Acceptor Splice Site ◽  
Exon 2 ◽  
Gene Level ◽  
Exon 1

Fourteen T4-binding globulin (TBG) variants have been identified at the gene level. They are all located in the coding region of the gene and 6 produce complete deficiency of TBG (TBG-CD). We now describe the first mutation in a noncoding region producing TBG-CD. The proband was treated for over 20 yr with L-T4 because of fatigue associated with a low concentration of serum total T4. Fifteen family members were studied showing low total T4 inherited as an X chromosome-linked trait, and affected males had undetectable TBG in serum. Sequencing of the entire coding region and promoter of the TBG gene revealed no abnormality. However, an A to G transition was found in the acceptor splice junction of intron II that produced a new HaeIII restriction site cosegregating with the TBG-CD phenotype. Sequencing exon 1 to exon 3 of TBG complementary DNA reverse transcribed from messenger RNA of skin fibroblasts from an affected male, confirmed a shift in the ag acceptor splice site. This results in the insertion of a G in exon 2 and causes a frameshift and a premature stop at codon 195. This early termination of translation predicts a truncated TBG lacking 201 amino acids.

Monogenic Syndromes with Congenital Heart Diseases in Newborns (Diagnostic Clues for Neonatologists): A Critical Analysis with Systematic Literature Review

2021 ◽  
Author(s):  
Raffaele Falsaperla ◽  
Valentina Giacchi ◽  
Maria Giovanna Aguglia ◽  
Janette Mailo ◽  
Maria Grazia Longo ◽  
...  
Keyword(s):  
Systematic Review ◽  
Congenital Heart ◽  
Heart Diseases ◽  
Cost Effective ◽  
Monogenic Disease ◽  
Chromosomal Anomalies ◽  
Genetic Syndrome ◽  
Wide Range ◽  
Major Congenital Anomaly ◽  
Genomic Disorders

AbstractCongenital heart disease (CHD), the most common major congenital anomaly, is associated with a genetic syndrome (chromosomal anomalies, genomic disorders, or monogenic disease) in 30% of patients. The aim of this systematic review is to evaluate if, in the neonatal setting, clinical clues that orient the diagnostic path can be identified. For this purpose, we revised the most frequent dysmorphic features described in newborns with CHD, comparing those associated with monogenic syndromes (MSG) with the ones reported in newborns with genomic disorders. For this systematic review according to PRISMA statement, we used PubMed, Medline, Google Scholar, Scopus database, and search terms related to CHD and syndrome. We found a wide range of dysmorphisms (ocular region, ears, mouth, and/or palate and phalangeal anomalies) detected in more than half of MSGs were found to be associated with CHDs, but those anomalies are also described in genomic rearrangements syndromes with equal prevalence. These findings confirm that etiological diagnosis in newborns is challenging, and only the prompt and expert recognition of features suggestive of genetic conditions can improve the selection of appropriate, cost-effective diagnostic tests. However, in general practice, it is crucial to recognize clues that can suggest the presence of a genetic syndrome, and neonatologists often have the unique opportunity to be the first to identify abnormalities in the neonate.

KIF3B gene silent variant leading to sperm morphology and motility defects and male infertility

2021 ◽  
Author(s):  
Raheleh Heydari ◽  
Mehrshad Seresht-Ahmadi ◽  
Shahab Mirshahvaladi ◽  
Marjan Sabbaghian ◽  
Anahita Mohseni-Meybodi
Keyword(s):  
Male Infertility ◽  
Protein Expression ◽  
Binding Site ◽  
Sperm Count ◽  
Critical Role ◽  
Coiled Coil ◽  
Control Group ◽  
Coding Region ◽  
Exon 2 ◽  
Coiled Coil Domain

Abstract Sperm structural and functional defects are leading causes of male infertility. Patients with immotile sperm disorders suffer from axoneme failure and show a significant reduction in sperm count. The kinesin family member 3B (KIF3B) is one of the genes involved in the proper formation of sperm with a critical role in intraflagellar and intramanchette transport. A part of exon 2 and exons 3–5 of the KIF3B encodes a protein coiled-coil domain that interacts with IFT20 from the IFT protein complex. In the present study, the coding region of KIF3B coiled-coil domain was assessed in 88 oligoasthenoteratozoospermic patients, and the protein expression was evaluated in the mature spermatozoa of the case and control groups using immunocytochemistry and western blotting. According to the results, there was no genetic variation in the exons 3–5 of the KIF3B, but a new A > T variant was identified within the exon 2 in 30 patients, where nothing was detected in the control group. In contrast to healthy individuals, significantly reduced protein expression was observable in oligoasthenoteratozoospermic (OAT) patients carrying variation where protein organization was disarranged, especially in the principal piece and midpiece of the sperm tail. Besides, the protein expression level was lower in the patients’ samples compared to that of the control group. According to the results of the present study the NM_004798.3:c.1032A > T, p.Pro344 = variant; which has been recently submitted to the Clinvar database; although synonymous, causes alterations in the transcription factor binding site, exon skipping, and also exonic splicing enhancer-binding site. Therefore, KIF3B can play an important role in spermatogenesis and the related protein reduction can cause male infertility.

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