scholarly journals A Second Hit Somatic (P.R905W) and a Novel Germline Intron-Mutation of TSC2 Gene is Found in Intestinal Lymphangioleiomyomatosis: A Case Report with Literature Review

2021 ◽  
Author(s):  
Bogyeong Han ◽  
Juhwan Lee ◽  
Yoon Jin Kwak ◽  
Hyun-Young Kim ◽  
Kwang Hoon Lee ◽  
...  
Keyword(s):  
Intron Retention ◽  
Pathological Examination ◽  
Autosomal Dominant Disorder ◽  
Oncogenic Mutation ◽  
Intronic Mutation ◽  
Abdominal Masses ◽  
Whole Transcriptome Sequencing ◽  
Intron Region ◽  
Intron Mutation ◽  
Relationship Of

Abstract Background: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder associated with germline mutations in TSC1 and TSC2, including exonic, intronic, or mosaic mutations. Gastrointestinal (GI) tract Lymphangioleiomyomatosis (LAM) is an extremely rare manifestation of TSC, with few reported cases. Herein, we aimed to determine the driver mutation, pathogenesis, and relationship of germline and somatic mutations of LAM through whole-genome sequencing (WGS) of the tumor and blood samples and whole transcriptome sequencing (WTS) analysis. Case presentation: A nine-year-old girl with a full-blown TSC presented with abdominal masses detected during a routine check-up. Resected intestinal masses were diagnosed as LAM by thorough pathological examination. Interestingly, the LAM presented a somatic TSC2 gene mutation in exon 24 (p.R905W, c.C2713T), and the patient had intron retention by a novel germline mutation in the intron region of TSC2 (chr16:2126489, C>G). Conclusion: Our case suggests that intron retention by a single nucleotide intronic mutation of TSC2 is sufficient to develop severe manifestations of TSC, but the development of LAM requires an additional somatic oncogenic mutation.

scholarly journals A second hit somatic (p.R905W) and a novel germline intron-mutation of TSC2 gene is found in intestinal lymphangioleiomyomatosis: a case report with literature review

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Bogyeong Han ◽  
Juhwan Lee ◽  
Yoon Jin Kwak ◽  
Hyun-Young Kim ◽  
Kwang Hoon Lee ◽  
...  
Keyword(s):  
Intron Retention ◽  
Pathological Examination ◽  
Autosomal Dominant Disorder ◽  
Oncogenic Mutation ◽  
Multiple Organs ◽  
Intronic Mutation ◽  
Abdominal Masses ◽  
Whole Transcriptome Sequencing ◽  
Intron Mutation ◽  
Relationship Of

Abstract Background Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by hamartomas in multiple organs associated with germline mutations in TSC1 and TSC2, including exonic, intronic, or mosaic mutations. Gastrointestinal (GI) tract Lymphangioleiomyomatosis (LAM) is an extremely rare manifestation of TSC, with few reported cases. Herein, we aimed to determine the driver mutation, pathogenesis, and relationship of germline and somatic mutations of LAM through whole-genome sequencing (WGS) of the tumor and blood samples and whole transcriptome sequencing (WTS) analysis. Case presentation A nine-year-old girl with a full-blown TSC presented with abdominal masses detected during a routine check-up. Resected intestinal masses were diagnosed as LAM by thorough pathological examination. Interestingly, the LAM presented a somatic TSC2 gene mutation in exon 24 (p.R905W, c.C2713T), and the patient had intron retention by a novel germline mutation in the intron region of TSC2 (chr16:2126489, C > G). Conclusion Our case suggests that intron retention by a single nucleotide intronic mutation of TSC2 is sufficient to develop severe manifestations of TSC, but the development of LAM requires an additional somatic oncogenic mutation of TSC2.

Intronic SMCHD1 variants in FSHD: testing the potential for CRISPR-Cas9 genome editing

2019 ◽  
Vol 56 (12) ◽  
pp. 828-837 ◽  
Author(s):  
Remko Goossens ◽  
Marlinde L van den Boogaard ◽  
Richard J L F Lemmers ◽  
Judit Balog ◽  
Patrick J van der Vliet ◽  
...  
Keyword(s):  
Genome Editing ◽  
Intron Retention ◽  
Wild Type ◽  
Repeat Array ◽  
D4z4 Repeat ◽  
Intronic Mutation ◽  
Whole Exome ◽  
Efficient Suppression ◽  
The Common ◽  
Chromatin Relaxation

BackgroundFacioscapulohumeral dystrophy (FSHD) is associated with partial chromatin relaxation of the DUX4 retrogene containing D4Z4 macrosatellite repeats on chromosome 4, and transcriptional de-repression of DUX4 in skeletal muscle. The common form of FSHD, FSHD1, is caused by a D4Z4 repeat array contraction. The less common form, FSHD2, is generally caused by heterozygous variants in SMCHD1.MethodsWe employed whole exome sequencing combined with Sanger sequencing to screen uncharacterised FSHD2 patients for extra-exonic SMCHD1 mutations. We also used CRISPR-Cas9 genome editing to repair a pathogenic intronic SMCHD1 variant from patient myoblasts.ResultsWe identified intronic SMCHD1 variants in two FSHD families. In the first family, an intronic variant resulted in partial intron retention and inclusion of the distal 14 nucleotides of intron 13 into the transcript. In the second family, a deep intronic variant in intron 34 resulted in exonisation of 53 nucleotides of intron 34. In both families, the aberrant transcripts are predicted to be non-functional. Deleting the pseudo-exon by CRISPR-Cas9 mediated genome editing in primary and immortalised myoblasts from the index case of the second family restored wild-type SMCHD1 expression to a level that resulted in efficient suppression of DUX4.ConclusionsThe estimated intronic mutation frequency of almost 2% in FSHD2, as exemplified by the two novel intronic SMCHD1 variants identified here, emphasises the importance of screening for intronic variants in SMCHD1. Furthermore, the efficient suppression of DUX4 after restoring SMCHD1 levels by genome editing of the mutant allele provides further guidance for therapeutic strategies.

The Relationship of Intrauterine Growth Restriction with Placental Pathologic Changes in Newborns

2020 ◽  
Author(s):  
Hossein Dalili ◽  
Fatemeh Sadat Nayeri ◽  
Seyed Reza Mirjalili ◽  
Seyyed Nasrollah Hossein ◽  
Alireza Abdollahi ◽  
...  
Keyword(s):  
Intrauterine Growth Restriction ◽  
Growth Restriction ◽  
Pathological Examination ◽  
Histological Changes ◽  
Intrauterine Growth ◽  
Study Population ◽  
The Mean ◽  
Relationship Of ◽  
The Relationship ◽  
Restriction Group

Introduction: Intrauterine growth restriction is a multifaceted problem and is associated with a significant increase in the level of morbidity and perinatal mortality. According to some studies, failure of the placenta is responsible for the most cases of intrauterine growth restriction. The aim of this study was to evaluate the placental pathologic changes in the intrauterine growth restriction (IUGR) samples and compare them with normal cases.   Methods: A study population consisted of 60 intrauterine growth restriction neonates and 60 normalized neonates born at Tehran Imam Khomeini Hospital between June 2016 and July 2017. The placenta was weighed, immediately after delivery, and the umbilical cord was separated, then stored in 10% formalin and sent for pathological examination as soon as possible. Data collection was performed according to the following items: the pathologist's report, the results of the infants' examination, and the data in the neonatal cases.   Results: The intrauterine growth restriction group showed a high frequency of placenta infarction (P < 0.001), inflammation of the villous (P < 0.001), villous fibrosis (P = 0.044), villous vascularization disorder (P = 0.001), prevalence of chorioamnionitis (P = 0.027), prevalence of Syncytiotrophoblastic knots (P < 0.001) and placental necrosis (P = 0.048) than normal group. However, the mean weight of the placenta (P < 0.001), the length and width of the macroscopic placenta changes was less (P < 0.001).   Conclusion: The results of the current study showed that a major part of the macroscopic and histological changes are detectable in the intrauterine growth restriction samples, which are considerably more common than normal, although they are not pathognomonic, but in the future, more accurate results can be obtained from more extensive studies.

scholarly journals A deep intronic mutation in AR gene causing androgen insensitivity syndrome: difficulties of diagnostics

2021 ◽  
Vol 67 (5) ◽  
pp. 48-52
Author(s):  
N. Y. Kalinchenko ◽  
V. M. Petrov ◽  
A. V. Panova ◽  
A. N. Tiulpakov
Keyword(s):  
Genetic Diagnosis ◽  
Androgen Insensitivity Syndrome ◽  
Splice Acceptor Site ◽  
Acceptor Site ◽  
Coding Region ◽  
Sex Development ◽  
Intronic Mutation ◽  
Androgen Resistance ◽  
Differences Of Sex Development ◽  
Intron Mutation

Partial androgen resistance syndrome (PAIS) is the most difficult form of disorders/differences of sex development 46,XY (DSD 46,XY) for choosing of patient management. To date, there are no clear biochemical criteria, especially before puberty, that allow differentiating PAIS from other PAIS-like forms of DSD 46, XY, and genetic verification of the partial form of AIS plays an important role. Meanwhile, according to the literature, mutations in the coding region of AR gene have not been identified in more than 50% of patients with suspected AIS. We performed an extensive analysis of the AR gene in a patient with clinical and laboratory signs of AIS and found a deep intron mutation in the AR gene (p. 2450–42G>A). This variant creates an alternative splice acceptor site resulted a disturbance of the AR function. These findings indicate the need for extensive genetic analysis in a cohort of patients with suspected CPA in the absence of mutations in the AR gene using standard methods of genetic diagnosis.

scholarly journals Severe congenital hypothyroidism due to a novel deep intronic mutation in the TSH receptor gene causing intron retention

2020 ◽  
Author(s):  
Stéphanie Larrivée-Vanier ◽  
Fabien Magne ◽  
Elwaseila Hamdoun ◽  
Anna Petryk ◽  
Zoha Kibar ◽  
...  
Keyword(s):  
Cell Surface ◽  
Exome Sequencing ◽  
Congenital Hypothyroidism ◽  
Transmembrane Domain ◽  
Intron Retention ◽  
Receptor Gene ◽  
Tsh Receptor ◽  
Intronic Mutation ◽  
Exome Analysis ◽  
Isoform Expression

Abstract In three Somalian siblings with severe nongoitrous congenital hypothyroidism, exome sequencing identified a variant in TSHR predicted to be benign in isoform 3 but leading to an intronic mutation in isoform 1 (NM_00369:c.692 + 130C&gt;A), which is the isoform expressed in the thyroid. This mutation creates a pseudo-exon that results in a protein that, if transcribed, would lack the transmembrane domain, thereby hampering its expression at the cell surface. Our findings illustrate that the interpretation of exome analysis requires knowledge of the relevant isoform expression and of the biology of the disease. This is the first description of a deep intronic mutation creating a pseudo-exon and inactivating the TSH receptor.

scholarly journals Impaired human hematopoiesis due to a cryptic intronic GATA1 splicing mutation

2019 ◽  
Vol 216 (5) ◽  
pp. 1050-1060 ◽  
Author(s):  
Nour J. Abdulhay ◽  
Claudia Fiorini ◽  
Jeffrey M. Verboon ◽  
Leif S. Ludwig ◽  
Jacob C. Ulirsch ◽  
...  
Keyword(s):  
Allelic Variation ◽  
Intron Retention ◽  
Splice Acceptor Site ◽  
Acceptor Site ◽  
Loss Of Function ◽  
Splice Acceptor ◽  
Blood Disorders ◽  
Functional Studies ◽  
Intronic Mutation ◽  
C Terminus

Studies of allelic variation underlying genetic blood disorders have provided important insights into human hematopoiesis. Most often, the identified pathogenic mutations result in loss-of-function or missense changes. However, assessing the pathogenicity of noncoding variants can be challenging. Here, we characterize two unrelated patients with a distinct presentation of dyserythropoietic anemia and other impairments in hematopoiesis associated with an intronic mutation in GATA1 that is 24 nucleotides upstream of the canonical splice acceptor site. Functional studies demonstrate that this single-nucleotide alteration leads to reduced canonical splicing and increased use of an alternative splice acceptor site that causes a partial intron retention event. The resultant altered GATA1 contains a five–amino acid insertion at the C-terminus of the C-terminal zinc finger and has no observable activity. Collectively, our results demonstrate how altered splicing of GATA1, which reduces levels of the normal form of this master transcription factor, can result in distinct changes in human hematopoiesis.

scholarly journals Novel Heterozygous LMNA Variants Causing Familial Partial Lipodystrophy, Dunnigan Variety

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A35-A35
Author(s):  
Akhilesh Wadhwa ◽  
Chandna Vasandani ◽  
Abhimanyu Garg
Keyword(s):  
Autosomal Dominant ◽  
Subcutaneous Fat ◽  
Conduction System ◽  
Cardiac Conduction ◽  
Autosomal Dominant Disorder ◽  
Partial Lipodystrophy ◽  
Total Cohort ◽  
Causal Variants ◽  
Familial Partial Lipodystrophy ◽  
Relationship Of

Abstract Familial partial lipodystrophy (FPLD) is a rare, mostly autosomal dominant disorder characterized by selective loss of subcutaneous fat from the extremities. Patients with FPLD are predisposed to insulin resistance, dyslipidemia, diabetes mellitus, cardiac abnormalities (coronary heart disease [CHD], cardiomyopathy and conduction system disorders) and hepatic steatosis. FPLD2 (the Dunnigan variety) is the most common subtype which is caused by heterozygous variants in the lamin A/C (LMNA) gene. Over 50 LMNA causal variants have been reported in patients with FPLD2, with p.R482W and p.R482Q comprising ~75% of the families. We report 5 novel LMNA variants (c.722T&gt;C, p.L241P; c.848A&gt;G, p.N283S; c.1396A&gt;G, p.N466D; c.1543A&gt;G, p.K515E; c.1744C&gt;A, p.R582S) in 5 families, where a female proband presented to us with moderately-severe FPLD, from among a total cohort of 264 FPLD2 families, with 259 families harboring other known pathogenic LMNA variants. The p.L241P variant was found in a 62-year-old female with a body mass index (BMI) of 28 kg/m2. She had hypertriglyceridemia. She is adopted and has two offsprings, who have not yet been examined and genotyped. The p.N283S variant was found in two males and two females from the same family (Age 40–74 y; BMI 18–45 kg/m2). Of these, only the 74-year-old female proband had clinical lipodystrophy, diabetes and hypertriglyceridemia. The other three subjects did not have lipodystrophy. Thus, this variant did not segregate with the phenotype of lipodystrophy in this family likely due to low penetrance or reduced clinical expressivity. The p.N466D variant was found in a 53-year-old female (BMI 26 kg/m2) who had diabetes and hypertriglyceridemia. The p.K515E variant was found in 4 females and 1 male who belonged to the same family (Age 29–62 y; BMI 19–26 kg/m2). All of them had lipodystrophy and hypertriglyceridemia and three of them had diabetes. The p.R582S variant was found in 3 males and one female who belonged to the same family (Age 19–76 y; BMI 16–30 kg/m2). All of them had lipodystrophy but only two of them had diabetes and hypertriglyceridemia. Eight of them had hypertension, three had CHD, one of them had acute pancreatitis and another one had a stroke. None of these patients had cardiomyopathy, cardiac conduction system defects or myopathy. In conclusion, we report genotype-phenotype relationship of 5 novel LMNA variants in patients presenting with FPLD2, with variable prevalence of diabetes, hypertriglyceridemia hypertension and CAD. None of these variants are associated with cardiomyopathy or myopathy or progeroid features. Our report adds to the allelic and clinical heterogeneity associated with LMNA variants.

scholarly journals Disseminated peritoneal leiomyomatosis: a case report and review of the literature

2021 ◽  
Vol 49 (8) ◽  
pp. 030006052110331
Author(s):  
Xu Liu ◽  
Yuchang Hu ◽  
Lu Chen ◽  
Quan Zhou
Keyword(s):  
Good Prognosis ◽  
Subsequent Pregnancy ◽  
Pathological Examination ◽  
Hormonal Stimulation ◽  
Abdominal Masses ◽  
Smooth Muscle Tumors ◽  
Leiomyomatosis Peritonealis Disseminata ◽  
History Of ◽  
Disseminated Peritoneal Leiomyomatosis

Disseminated peritoneal leiomyomatosis (DPL), also known as leiomyomatosis peritonealis disseminata, is a rare disease characterized by multiple benign smooth muscle tumors proliferating along the peritoneal surfaces. The cause of the disease is unclear, and possible factors include iatrogenic and hormonal stimulation. The patient was a 41-year-old Chinese woman with a history of laparoscopic myomectomy and subsequent pregnancy. Multiple abdominal masses were identified and required surgical intervention. The patient had no tenderness or other discomfort. The clinical and imaging diagnosis was gastrointestinal stromal tumor, but DPL was confirmed by postoperative pathological examination. The patient had a good prognosis, and no recurrence was observed during follow-up. Iatrogenic and hormonal stimulation leading to DPL is very rare, and we believe that multiple factors led to DPL in this case. Clinicians should be aware of such potential patients.

The relationship of the scleractinian corals to the rugose corals

Paleobiology ◽  
1980 ◽  
Vol 6 (02) ◽  
pp. 146-160 ◽  
Author(s):  
William A. Oliver
Keyword(s):  
Critical Points ◽  
Scleractinian Corals ◽  
Convincing Evidence ◽  
Early Triassic ◽  
Rugose Corals ◽  
History Of ◽  
The Subject ◽  
Relationship Of ◽  
The Relationship ◽  
Biologic Factors

The Mesozoic-Cenozoic coral Order Scleractinia has been suggested to have originated or evolved (1) by direct descent from the Paleozoic Order Rugosa or (2) by the development of a skeleton in members of one of the anemone groups that probably have existed throughout Phanerozoic time. In spite of much work on the subject, advocates of the direct descent hypothesis have failed to find convincing evidence of this relationship. Critical points are:(1) Rugosan septal insertion is serial; Scleractinian insertion is cyclic; no intermediate stages have been demonstrated. Apparent intermediates are Scleractinia having bilateral cyclic insertion or teratological Rugosa.(2) There is convincing evidence that the skeletons of many Rugosa were calcitic and none are known to be or to have been aragonitic. In contrast, the skeletons of all living Scleractinia are aragonitic and there is evidence that fossil Scleractinia were aragonitic also. The mineralogic difference is almost certainly due to intrinsic biologic factors.(3) No early Triassic corals of either group are known. This fact is not compelling (by itself) but is important in connection with points 1 and 2, because, given direct descent, both changes took place during this only stage in the history of the two groups in which there are no known corals.

Skeletal elements of crinoid echinoderms: High-resolution structural and microanalytical results

1983 ◽  
Vol 41 ◽  
pp. 194-195
Author(s):  
D. F. Blake ◽  
L. F. Allard ◽  
D. R. Peacor
Keyword(s):  
High Resolution ◽  
Marine Invertebrates ◽  
Sea Urchins ◽  
Structural Features ◽  
Sea Stars ◽  
High Resolution Tem ◽  
Relationship Of ◽  
The Relationship ◽  
Insight Into

Echinodermata is a phylum of marine invertebrates which has been extant since Cambrian time (c.a. 500 m.y. before the present). Modern examples of echinoderms include sea urchins, sea stars, and sea lilies (crinoids). The endoskeletons of echinoderms are composed of plates or ossicles (Fig. 1) which are with few exceptions, porous, single crystals of high-magnesian calcite. Despite their single crystal nature, fracture surfaces do not exhibit the near-perfect {10.4} cleavage characteristic of inorganic calcite. This paradoxical mix of biogenic and inorganic features has prompted much recent work on echinoderm skeletal crystallography. Furthermore, fossil echinoderm hard parts comprise a volumetrically significant portion of some marine limestones sequences. The ultrastructural and microchemical characterization of modern skeletal material should lend insight into: 1). The nature of the biogenic processes involved, for example, the relationship of Mg heterogeneity to morphological and structural features in modern echinoderm material, and 2). The nature of the diagenetic changes undergone by their ancient, fossilized counterparts. In this study, high resolution TEM (HRTEM), high voltage TEM (HVTEM), and STEM microanalysis are used to characterize tha ultrastructural and microchemical composition of skeletal elements of the modern crinoid Neocrinus blakei.

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