scholarly journals A Novel Mutation in GP1BB Reveals the Role of the Cytoplasmic Domain of GPIbβ in the Pathophysiology of Bernard-Soulier Syndrome and GPIb-IX Complex Assembly

2021 ◽  
Vol 22 (19) ◽  
pp. 10190
Author(s):  
Serena Barozzi ◽  
Valeria Bozzi ◽  
Daniela De De Rocco ◽  
Tania Giangregorio ◽  
Patrizia Noris ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Novel Mutation ◽  
Cytoplasmic Domain ◽  
Bleeding Tendency ◽  
Dominant Effect ◽  
Pathogenic Variants ◽  
New Information ◽  
Genes Encoding ◽  
Bernard Soulier Syndrome

Bernard-Soulier syndrome (BSS) is an autosomal-recessive bleeding disorder caused by biallelic variants in the GP1BA, GP1BB, and GP9 genes encoding the subunits GPIbα, GPIbβ, and GPIX of the GPIb-IX complex. Pathogenic variants usually affect the extracellular or transmembrane domains of the receptor subunits. We investigated a family with BSS caused by the homozygous c.528_550del (p.Arg177Serfs*124) variant in GP1BB, which is the first mutation ever identified that affects the cytoplasmic domain of GPIbβ. The loss of the intracytoplasmic tail of GPIbβ results in a mild form of BSS, characterized by only a moderate reduction of the GPIb-IX complex expression and mild or absent bleeding tendency. The variant induces a decrease of the total platelet expression of GPIbβ; however, all of the mutant subunit expressed in platelets is correctly assembled into the GPIb-IX complex in the plasma membrane, indicating that the cytoplasmic domain of GPIbβ is not involved in assembly and trafficking of the GPIb-IX receptor. Finally, the c.528_550del mutation exerts a dominant effect and causes mild macrothrombocytopenia in heterozygous individuals, as also demonstrated by the investigation of a second unrelated pedigree. The study of this novel GP1BB variant provides new information on pathophysiology of BSS and the assembly mechanisms of the GPIb-IX receptor.

Molecular genetic diagnostics of Bardet-Biedl syndrome with an MPS-panel

2021 ◽  
pp. 26-35
Author(s):  
М.Д. Орлова ◽  
П. Гундорова ◽  
А.В. Поляков
Keyword(s):  
Autosomal Recessive ◽  
Molecular Genetic ◽  
Autosomal Recessive Disorder ◽  
Genetic Diagnostics ◽  
Bardet Biedl Syndrome ◽  
Pathogenic Variants ◽  
Development Delay ◽  
Molecular Genetic Diagnostics ◽  
First Time

Синдром Барде-Бидля - аутосомно-рецессивное заболевание, характеризующееся ожирением, пигментной дегенерацией сетчатки, полидактилией, задержкой психоречевого развития и структурными повреждениями почек. В работе представлены результаты применения МПС-панели, включающей кодирующие последовательности и прилегающие интронные области 21 гена, ассоциированного с синдромом Барде-Бидля. Впервые была проведена молекулярно-генетическая диагностика в группе из сорока российских пациентов с синдромом Барде-Бидля из неродственных семей. В результате исследования удалось подтвердить диагноз молекулярно-генетическим методом у 40% пациентов (n=16). В генах BBS1, BBS7 и BBS10 встретились повторяющиеся варианты. Частота встречаемости патогенных и вероятно патогенных вариантов в генах BBS1 и BBS10 у российских пациентов соответствует зарубежным данным. Варианты в гене BBS7 встретились у пяти человек, у четырех из них был обнаружен патогенный вариант c.1967_1968delTAinsC, не встречающийся в других популяциях. Результаты, представленные в статье, показывают значительный вклад в заболеваемость синдромом Барде-Бидля в российской популяции патогенных вариантов в гене BBS7. Bardet-Biedl syndrome is an autosomal recessive disorder characterized by obesity, retinitis pigmentosa, polydactyly, development delay, and structural kidney defects. This study shows the results of using an MPS panel that includes coding sequences and intronic areas of 21 genes associated with Bardet-Biedl syndrome. For the first time molecular genetic testing has been provided for the group of 40 Russian patiens with Bardet-Biedl syndrome from unrelated families. As a result of the testing, diagnoses were confirmed for 40% of the patients (n=16). The genes BBS1, BBS7, BBS10 had recurrent variants. The frequency of pathogenic and likely pathogenic variants in the genes BBS1 and BBS10 among Russian patients matches the research data in other countries. Variants in the BBS7 gene were found for five people, four of them had a pathogenic variant c.1967_1968delTAinsC, which is not present among other populations. Results provided in this article show the significant role of pathogenic variants in the BBS7 gene in patients with Bardet-Biedl syndrome in Russian population.

Gene structure of urea transporters

2003 ◽  
Vol 284 (1) ◽  
pp. F3-F10 ◽  
Author(s):  
Serena M. Bagnasco
Keyword(s):  
Transcriptional Control ◽  
Molecular Mechanisms ◽  
Physiological Role ◽  
Renal Physiology ◽  
The Past ◽  
New Information ◽  
Lower Vertebrates ◽  
Genes Encoding ◽  
Concentrate Urine

Urea plays various roles in the biology of diverse organisms. The past decade has produced new information on the molecular structure of several urea transporters in various species. Availability of DNA probes has revealed that the presence of urea transporters is not confined to the mammalian kidney but is also evident in testis and brain, raising new questions about the possible physiological role of urea in these organs. Cloning of the genes encoding the two closely related mammalian urea transporters UT-A and UT-B has helped in identifying molecular mechanisms affecting expression of urea transporters in the kidney, such as transcriptional control for UT-A abundance. On the basis of analysis of genomic sequences of individuals lacking the UT-B transporter, mutations have been found that explain deficits in their capacity to concentrate urine. More urea transporters are being characterized in marine organisms and lower vertebrates, and studying the role and regulation of urea transport from an evolutionary perspective can certainly enrich our understanding of renal physiology.

Glanzmann’s Thrombasthenia: Identification of 19 New Mutations in 30 Patients

2002 ◽  
Vol 87 (06) ◽  
pp. 1034-1042 ◽  
Author(s):  
Giovanna D’Andrea ◽  
Donatella Colaizzo ◽  
Gennaro Vecchione ◽  
Elvira Grandone ◽  
Giovanni Di Minno ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Autosomal Recessive ◽  
Wide Spectrum ◽  
Bleeding Tendency ◽  
Missense Mutations ◽  
Conserved Residues ◽  
Glanzmann’S Thrombasthenia ◽  
Glanzmann's Thrombasthenia ◽  
New Mutations

SummaryGlanzmann’s thrombasthenia (GT) is a genetically heterogeneous autosomal recessive syndrome associated with a bleeding tendency. To elucidate molecular basis of GT we have screened for mutations 30 GT patients. On the whole, 21 different candidate causal mutations, 17 in the αIIb and 4 in the β3 gene have been found. Only two (αIIb Pro145Ala and IVS3(−3)-418del) have been previously reported. Nine mutations (42.9%) were likely to produce truncated proteins, whereas the remaining 12 were missense mutations that affected highly conserved residues in αIIb and β3 genes. Six mutations were found in different patients suggesting a possible founder effect. The wide spectrum of expressivity, ranging from mild to severe also among patients carrying the same mutations, provided evidence for a role of different loci or circumstantial factors. In conclusion, we have identified a spectrum of unreported mutations that may be of value to unravel the role of specific regions of αIIb and β3 genes.

scholarly journals Short QT Syndrome: A Comprehensive Genetic Interpretation and Clinical Translation of Rare Variants

2019 ◽  
Vol 8 (7) ◽  
pp. 1035 ◽  
Author(s):  
Oscar Campuzano ◽  
Anna Fernandez-Falgueras ◽  
Ximena Lemus ◽  
Georgia Sarquella-Brugada ◽  
Sergi Cesar ◽  
...  
Keyword(s):  
Rare Variants ◽  
Short Qt Syndrome ◽  
Pathogenic Variants ◽  
Qt Intervals ◽  
Genetic Interpretation ◽  
Genes Encoding ◽  
Qt Syndrome ◽  
Genetics And Genomics ◽  
Exhaustive Study

Short QT syndrome, one of the most lethal entities associated with sudden cardiac death, is a rare genetic disease characterized by short QT intervals detected by electrocardiogram. Several genetic variants are causally linked to the disease, but there has yet to be a comprehensive analysis of variants among patients with short QT syndrome. To fill this gap, we performed an exhaustive study of variants currently catalogued as deleterious in short QT syndrome according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Analysis of the 32 variants described in the literature determined that only nine (28.12%) have a conclusive pathogenic role. All definitively pathogenic variants are located in KCNQ1, KCNH2, or KCNJ2; three genes encoding potassium channels. Other variants located in genes encoding calcium or sodium channels are associated with electrical alterations concomitant with shortened QT intervals but do not guarantee a diagnosis of short QT syndrome. We recommend caution regarding previously reported variants classified as pathogenic. An exhaustive re-analysis is necessary to clarify the role of each variant before routinely translating genetic findings to the clinical setting.

scholarly journals TBC1D24 emerges as an important contributor to progressive postlingual dominant hearing loss

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dominika Oziębło ◽  
Marcin L. Leja ◽  
Michal Lazniewski ◽  
Anna Sarosiak ◽  
Grażyna Tacikowska ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Autosomal Recessive ◽  
High Frequencies ◽  
Important Contributor ◽  
Pathogenic Variants ◽  
Age Related ◽  
Functional Consequences ◽  
Protein Variants ◽  
Autosomal Recessive Manner

AbstractSeveral TBC1D24 variants are causally involved in the development of profound, prelingual hearing loss (HL) and different epilepsy syndromes inherited in an autosomal recessive manner. Only two TBC1D24 pathogenic variants have been linked with postlingual progressive autosomal dominant HL (ADHL). To determine the role of TBC1D24 in the development of ADHL and to characterize the TBC1D24-related ADHL, clinical exome sequencing or targeted multigene (n = 237) panel were performed for probands (n = 102) from multigenerational ADHL families. In four families, TBC1D24-related HL was found based on the identification of three novel, likely pathogenic (c.553G>A, p.Asp185Asn; c.1460A>T, p. His487Leu or c.1461C>G, p.His487Gln) and one known (c.533C>T, p.Ser178Leu) TBC1D24 variant. Functional consequences of these variants were characterized by analyzing the proposed homology models of the human TBC1D24 protein. Variants not only in the TBC (p.Ser178Leu, p.Asp185Asn) but also in the TLDc domain (p.His487Gln, p.His487Leu) are involved in ADHL development, the latter two mutations probably affecting interactions between the domains. Clinically, progressive HL involving mainly mid and high frequencies was observed in the patients (n = 29). The progression of HL was calculated by constructing age-related typical audiograms. TBC1D24-related ADHL originates from the cochlear component of the auditory system, becomes apparent usually in the second decade of life and accounts for approximately 4% of ADHL cases. Given the high genetic heterogeneity of ADHL, TBC1D24 emerges as an important contributor to this type of HL.

scholarly journals Identification of a novel mutation in the autoimmune regulator (AIRE-1) gene in a French family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy

2001 ◽  
pp. 347-351 ◽  
Author(s):  
P Saugier-Veber ◽  
N Drouot ◽  
LM Wolf ◽  
JM Kuhn ◽  
T Frebourg ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Clinical Symptoms ◽  
Novel Mutation ◽  
Autosomal Recessive Inheritance ◽  
Chronic Mucocutaneous Candidiasis ◽  
Autoimmune Regulator ◽  
Autoimmune Polyendocrinopathy ◽  
Plant Homeodomain ◽  
French Family

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is clinically characterized by the presence of two of the three major clinical symptoms: Addison's disease and/or hypoparathyroidism and/or chronic mucocutaneous candidiasis. Because of its autosomal recessive inheritance, this rare disorder constitutes an interesting model for understanding the molecular background of autoimmunity. Recently, mutations in the autoimmune regulator (AIRE-1) gene have been identified in APECED patients. Here we report, in a large French APECED family, the identification of a novel AIRE-1 missense mutation (Pro326Leu) in association with the Arg257Stop mutation which is detected in more than 80% of mutant Finnish AIRE-1 alleles. This Pro326Leu substitution occurs in the first plant homeodomain (PHD)-type zinc-finger domain of the protein which has been identified in a number of nuclear proteins involved in chromatin-mediated transcriptional regulation, such as ATRX, TIF1, KRIP-1 and Mi-2 autoantigen. This mutation highlights the key role of this amino acid in the structure of the PHD domain and confirms that exon 8 constitutes a mutational hotspot.

scholarly journals Recurrent Synovitis of Hip and MEFV Gene Related Arthritis in Children

2019 ◽  
Author(s):  
Farhad Salehzadeh ◽  
Mehrdad Mirzarahimi
Keyword(s):  
Autosomal Recessive ◽  
Mefv Gene ◽  
Gene Mutations ◽  
Inflammatory Disorder ◽  
Hip Joints ◽  
Mefv Mutations ◽  
Pathogenic Variants ◽  
Pathologic Findings ◽  
Mediterranean Fever

Abstract Background: Familial Mediterranean fever (FMF) is an autosomal recessive inherited auto inflammatory disorder. Arthritis is the presenting finding of FMF in some patients, and sometimes it remains as the major manifestation of the disorder. This study reports three non-FMF patients with heterozygous MEFV gene mutations and an extraordinary arthritis as a recurrent synovitis of hip (RSH) Methods: During 16-years from 2003 to 2019 at pediatric rheumatologic clinic among 195 recorded files, 3 patients with diagnosis of recurrent synovitis of hip (RSH) were reviewed thoroughly. Peripheral blood was collected from patients and the samples were screened for the 12 common MEFV gene pathogenic variants. Results: This study included three patients, two female and one male with relapsing arthritis that has been located on hip joints as a sole manifestation and pathologic findings of MEFV mutations as follow: A744S, V726A, and R761H. Conclusion: On the basis of possible role of MEFV gene in different rheumatic disease RSH could be considered as a MEFV gene related arthritis. Key words: FMF, MEFV gene, Recurrent synovitis of hip in children

Coagulation Dynamics in Factor V Deficiency: A Family Study, with a Note on the Occurrence of Thrombophlebitis, ,

1965 ◽  
Vol 13 (02) ◽  
pp. 500-515 ◽  
Author(s):  
Sherwood P. Miller ◽  
Keyword(s):  
Autosomal Recessive ◽  
Recessive Gene ◽  
Coagulation Factors ◽  
Severe Bleeding ◽  
Factor V ◽  
Bleeding Tendency ◽  
Clinically Normal ◽  
Sequence Of Events ◽  
Factor V Deficiency

Summary1. A family with congenital proaccelerin (factor V) deficiency is here reported. The mode of inheritance appears to be by means of an autosomal recessive gene. The homozygous propositus (proaccelerin less than 2% of normal) had a life-long, moderately severe, bleeding tendency. The heterozygotes (proaccelerin 45 to 66%) were clinically normal.2. Studies on the rate of consumption of coagulation factors during blood clotting revealed normal consumption of antihemophilic globulin (factor VIII), but defective consumption of prothrombin (II) in the propositus. This indicated the entry of proaccelerin into the clotting process between the stages at which antihemophilic globulin and prothrombin are involved. Five of the seven heterozygotes studied showed a similar pattern. These findings are consistent with current theories of the role of proaccelerin in the normal sequence of events in the coagulation scheme.3. The propositus had an episode of thrombosis of the deep saphenous vein which is apparently a unique occurence in the literature of proaccelerin deficiency.

DNA methylation in satellite repeats disorders

2019 ◽  
Vol 63 (6) ◽  
pp. 757-771 ◽  
Author(s):  
Claire Francastel ◽  
Frédérique Magdinier
Keyword(s):  
Dna Methylation ◽  
Human Genome ◽  
Repetitive Dna ◽  
Dna Sequences ◽  
Satellite Repeats ◽  
Tremendous Progress ◽  
Genes Encoding ◽  
Dna Elements ◽  
Near Future

Abstract Despite the tremendous progress made in recent years in assembling the human genome, tandemly repeated DNA elements remain poorly characterized. These sequences account for the vast majority of methylated sites in the human genome and their methylated state is necessary for this repetitive DNA to function properly and to maintain genome integrity. Furthermore, recent advances highlight the emerging role of these sequences in regulating the functions of the human genome and its variability during evolution, among individuals, or in disease susceptibility. In addition, a number of inherited rare diseases are directly linked to the alteration of some of these repetitive DNA sequences, either through changes in the organization or size of the tandem repeat arrays or through mutations in genes encoding chromatin modifiers involved in the epigenetic regulation of these elements. Although largely overlooked so far in the functional annotation of the human genome, satellite elements play key roles in its architectural and topological organization. This includes functions as boundary elements delimitating functional domains or assembly of repressive nuclear compartments, with local or distal impact on gene expression. Thus, the consideration of satellite repeats organization and their associated epigenetic landmarks, including DNA methylation (DNAme), will become unavoidable in the near future to fully decipher human phenotypes and associated diseases.

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