Novel compound heterozygous Thyroglobulin mutations c.745+1G>A/c.7036+2T>A associated with congenital goiter and hypothyroidism in a Vietnamese family. Identification of a new cryptic 5′ splice site in the exon 6

2015 ◽  
Vol 404 ◽  
pp. 102-112 ◽  
Author(s):  
Cintia E. Citterio ◽  
Cecilia M. Morales ◽  
Natacha Bouhours-Nouet ◽  
Gloria A. Machiavelli ◽  
Elena Bueno ◽  
...  
Keyword(s):  
Splice Site ◽  
Compound Heterozygous ◽  
Congenital Goiter

scholarly journals New Compound Heterozygous Splice Site Mutations of the Skeletal Muscle Ryanodine Receptor (RYR1) Gene Manifest Fetal Akinesia: A Linkage with Congenital Myopathies

2020 ◽  
Vol 11 (2) ◽  
pp. 104-109
Author(s):  
Nebojsa Zecevic ◽  
Vladimir Arsenijevic ◽  
Emmanouil Manolakos ◽  
Ioannis Papoulidis ◽  
Georgios Theocharis ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Ryanodine Receptor ◽  
Splice Site ◽  
Compound Heterozygous ◽  
Congenital Myopathies

Autosomal Recessive Axonal Form of Charcot-Marie-Tooth Disease Caused by Compound Heterozygous 3′-Splice Site and Ser130Cys Mutation in theGDAP1Gene

2005 ◽  
Vol 36 (3) ◽  
pp. 206-209 ◽  
Author(s):  
D. Kabzińska ◽  
A. Kochański, ◽  
H. Drac ◽  
B. Ryniewicz ◽  
K. Rowińska-Marcińska ◽  
...  
Keyword(s):  
Splice Site ◽  
Autosomal Recessive ◽  
Compound Heterozygous ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

scholarly journals Congenital Goiter with Hypothyroidism Caused by a 5′ Splice Site Mutation in the Thyroglobulin Gene

Thyroid ◽  
2001 ◽  
Vol 11 (7) ◽  
pp. 685-690 ◽  
Author(s):  
Héctor M. Targovnik ◽  
Carina M. Rivolta ◽  
Fernando M. Mendive ◽  
Christian M. Moya ◽  
Jussara Vono ◽  
...  
Keyword(s):  
Splice Site ◽  
Splice Site Mutation ◽  
Site Mutation ◽  
Congenital Goiter ◽  
Thyroglobulin Gene

scholarly journals Clear evidence of LAMA5 gene biallelic truncating variants causing infantile nephrotic syndrome

Kidney360 ◽  
2021 ◽  
pp. 10.34067/KID.0004952021
Author(s):  
Yukimasa Taniguchi ◽  
China Nagano ◽  
Kiyotoshi Sekiguchi ◽  
Atsushi Tashiro ◽  
Noriko Sugawara ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Splice Site ◽  
Japanese Patients ◽  
Compound Heterozygous ◽  
Missense Variants ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variants ◽  
Infantile Nephrotic Syndrome ◽  
Splice Site Variant

Background: Pathogenic variants in single genes encoding podocyte-associated proteins have been implicated in about 30% of steroid resistant nephrotic syndrome (SRNS) patients in children. However, LAMA5 gene biallelic variants have been identified in only 7 patients so far, and most are missense variants of unknown significance. Furthermore, no functional analysis had been conducted for all but one of these variants. Here, we report three patients with LAMA5 gene biallelic truncating variants manifesting infantile nephrotic syndrome and one SRNS case with biallelic LAMA5 missense variants. Methods: We conducted comprehensive gene screening of Japanese patients with severe proteinuria. Using targeted next-generation sequencing, 62 podocyte-related genes were screened in 407 unrelated patients with proteinuria. For the newly discovered LAMA5 variants, we conducted in vitro heterotrimer formation assays. Results: Biallelic truncating variants in the LAMA5 gene (NM_005560) were detected in 3 patients from 2 families. All patients presented with proteinuria within 6 months of age. Patients 1 and 2 were siblings possessing a nonsense variant (c.9232C>T, p.(Arg3078*)) and a splice site variant (c.1282+1G>A) that led to exon 9 skipping and a frameshift. Patient 3 had a remarkable irregular contour of the glomerular basement membrane. She was subsequently found to have a nonsense variant (c.8185C>T, p.(Arg2720*)) and the same splice site variant in patients 1 and 2. By in vitro heterotrimer formation assays, both truncating variants produced smaller laminin α5 proteins that nevertheless formed trimers with laminin β1 and γ1 chains. Patient 4 showed SRNS at the age of eight and carried compound heterozygous missense variants (c.1493C>T, p.(Ala498Val) and c.8399G>A, p.(Arg2800His)). Conclusions: Our patients showed clear evidence of biallelic LAMA5 truncating variants causing infantile nephrotic syndrome. We also discerned the clinical and pathological characteristics observed in LAMA5-related nephropathy. LAMA5 variant screening should be performed in congenital/infantile nephrotic syndrome patients.

Two Distinct Novel Splice Site Mutations in a Compound Heterozygous Patient with Protein S Deficiency

1997 ◽  
Vol 77 (01) ◽  
pp. 014-020 ◽  
Author(s):  
Tomio Yamazaki ◽  
Akira Katsumi ◽  
Yoshihiro Okamoto ◽  
Toshio Takafuta ◽  
Shinobu Tsuzuki ◽  
...  
Keyword(s):  
Splice Site ◽  
Protein S ◽  
Mutant Protein ◽  
Compound Heterozygous ◽  
Protein S Deficiency ◽  
Acceptor Splice Site ◽  
Mrna Accumulation ◽  
S Deficiency ◽  
Heterozygous Patient

SummaryGenetic analysis revealed two distinct novel splice site mutations in a compound heterozygous patient with protein S deficiency. The paternal mutation was a G-to-T transition at position -1 of the acceptor splice site of intron N (Mutation I), and the maternal mutation was a G-to-C transversion at position -1 of the donor splice site of intron C (Mutation II). Both splice site mutations decreased the mutated mRNA accumulation to the same extent, approximately 40% of the normal mRNA. However, the mutations were associated with different phenotypical expressions: the paternal mutant protein S was not detected in vivo, while the maternal mutant protein S was present in the plasma in reduced quantity. Because Mutation I caused a cryptic splicing in the mutated mRNA, resulting in a reading frameshift and premature termination, the predicted mutant protein S might be highly unstable. In contrast, Mutation II led to the substitution of Val46 by Leu, which might be much less deleterious for the synthesis, secretion and stability of the predicted mutant protein S. It was supposed that the different post-translational metabolisms produced the distinct phenotypical expressions of the mutations.

Novel aberrant splicings caused by a splice site mutation (IVS1a+5g>a) in F7 gene

2005 ◽  
Vol 93 (06) ◽  
pp. 1077-1081 ◽  
Author(s):  
Qihua Fu ◽  
Xuefeng Wang ◽  
Yiqun Hu ◽  
Zhenyi Wang ◽  
Qiulan Ding ◽  
...  
Keyword(s):  
Splice Site ◽  
Coagulation Factor ◽  
Factor Vii ◽  
Heterozygous Mutation ◽  
Alternative Transcript ◽  
Compound Heterozygous ◽  
Nucleotide Position ◽  
Coagulation Activity ◽  
Exon 2 ◽  
Coagulation Factor Vii

SummaryLow FVII coagulant activity (FVII:C 8.2%) and antigen level (FVII:Ag 34.1%) in a 46-year-old Chinese male led to a diagnosis of coagulation factor VII (FVII) deficiency. Compound heterozygous mutations were identified in his F7 gene:a G to A transition in the 5’ donor splice site of intron 1a (IVS1a+5g>a) and a T to G transition at the nucleotide position 10961 in exon 8, resulting in a His to Gln substitution at amino acid residue 348. An analysis of ectopic transcripts of F7 in the leukocytes of the patient reveals that the mutation (IVS1a+5g>a) is associated with two novel aberrant patterns of splicing. The predominant alternative transcript removes exon 2, but retains intron 3, which shifts the reading frame and predicts a premature translation termination at the nucleotide positions 2–4 in intron 3. The minor alternative transcript skips both exon 2 and exon 3 (FVII Δ2, 3), leading to an in-frame deletion of the propeptide and γ-carboxylated glutamic acid (Gla) domains of mature FVII protein. In vitro expression studies of the alternative transcript FVII Δ2, 3 by transient transfection of HEK 293 cells with PcDNA 3.1(-) expression vector showed that although the mutant protein could be secreted, no pro-coagulation activity was detected. The coexistence of the two abnormal transcripts and a heterozygous mutation His348Gln, explained the patient’s phenotype.

scholarly journals Heterozygosis for CYP21A2 mutation considered as 21-hydroxylase deficiency in neonatal screening

2008 ◽  
Vol 52 (8) ◽  
pp. 1388-1392 ◽  
Author(s):  
Fernanda Caroline Soardi ◽  
Sofia Helena V. Lemos-Marini ◽  
Fernanda Borchers Coeli ◽  
Víctor Gonçalves Maturana ◽  
Márcia Duarte Barbosa da Silva ◽  
...  
Keyword(s):  
Splice Site ◽  
Neonatal Screening ◽  
Compound Heterozygous ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Molecular Features ◽  
Molecular Studies ◽  
17 Hydroxyprogesterone ◽  
21 Hydroxylase Deficiency ◽  
Intron 4

Steroid 21-hydroxylase deficiency (21-OHD) accounts for more than 90% of congenital adrenal hyperplasia. CAH newborn screening, in general, is based on 17-hydroxyprogesterone dosage (17-OHP), however it is complicated by the fact that healthy preterm infants have high levels of 17-OHP resulting in false positive cases. We report on molecular features of a boy born pre-term (GA = 30 weeks; weight = 1,390 g) with elevated levels of 17-OHP (91.2 nmol/L, normal < 40) upon neonatal screening who was treated as having CAH up to the age of 8 months. He was brought to us for molecular diagnosis. Medication was gradually suspended and serum 17-OHP dosages mantained normal. The p.V281L mutation was found in compound heterozygous status with a group of nucleotide alterations located at the 3' end intron 4 and 5' end exon 5 corresponding to the splice site acceptor region. Molecular studies continued in order to exclude the possibility of a nonclassical 21-OHD form. The group of three nucleotide changes was demonstrated to be a normal variant since they failed to interfere with the normal splicing process upon minigene studies.

scholarly journals Genetic Spectrum of Syndromic and Non-Syndromic Hearing Loss in Pakistani Families

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1329
Author(s):  
Julia Doll ◽  
Barbara Vona ◽  
Linda Schnapp ◽  
Franz Rüschendorf ◽  
Imran Khan ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Exome Sequencing ◽  
Splice Site ◽  
Genetic Heterogeneity ◽  
Bioinformatics Analysis ◽  
Molecular Genetic ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Syndromic Hearing Loss ◽  
Pakistani Families

The current molecular genetic diagnostic rates for hereditary hearing loss (HL) vary considerably according to the population background. Pakistan and other countries with high rates of consanguineous marriages have served as a unique resource for studying rare and novel forms of recessive HL. A combined exome sequencing, bioinformatics analysis, and gene mapping approach for 21 consanguineous Pakistani families revealed 13 pathogenic or likely pathogenic variants in the genes GJB2, MYO7A, FGF3, CDC14A, SLITRK6, CDH23, and MYO15A, with an overall resolve rate of 61.9%. GJB2 and MYO7A were the most frequently involved genes in this cohort. All the identified variants were either homozygous or compound heterozygous, with two of them not previously described in the literature (15.4%). Overall, seven missense variants (53.8%), three nonsense variants (23.1%), two frameshift variants (15.4%), and one splice-site variant (7.7%) were observed. Syndromic HL was identified in five (23.8%) of the 21 families studied. This study reflects the extreme genetic heterogeneity observed in HL and expands the spectrum of variants in deafness-associated genes.

scholarly journals Predicting Phenotype in Steroid 21-Hydroxylase Deficiency? Comprehensive Genotyping in 155 Unrelated, Well Defined Patients from Southern Germany

2000 ◽  
Vol 85 (3) ◽  
pp. 1059-1065 ◽  
Author(s):  
Nils Krone ◽  
Andreas Braun ◽  
Adelbert Anton Roscher ◽  
Dietrich Knorr ◽  
Hans Peter Schwarz
Keyword(s):  
Splice Site ◽  
Splice Site Mutation ◽  
Compound Heterozygous ◽  
Site Mutation ◽  
Hydroxylase Deficiency ◽  
Salt Wasting ◽  
Severe Mutation ◽  
Heterozygous Form ◽  
21 Hydroxylase Deficiency ◽  
Intron 2

Abstract Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders. CAH is most often caused by deficiency of steroid 21-hydroxylase. The frequency of CYP21-inactivating mutations and the genotype-phenotype relationship were characterized in 155 well defined unrelated CAH patients. We were able to elucidate 306 of 310 disease-causing alleles (diagnostic sensitivity, 98.7%). The most frequent mutation was the intron 2 splice site mutation (30.3%), followed by gene deletions (20.3%), the I172N mutation (19.7%) and large gene conversions (7.1%). Five point mutations were detected that have not been described in other CAH cohorts. Genotypes were categorized in 4 mutation groups (null, A, B, and C) according to their predicted functional consequences and compared to the clinical phenotype. The positive predictive value for null mutations (ppvnull) was 100%, as all patients with these mutations had a salt-wasting phenotype. In mutation group A (intron 2 splice site mutation in homozygous or heterozygous form with a null mutation), the ppvA to manifest with salt-wasting CAH was 90%. In group B predicted to result in simple virilizing CAH (I172N in homozygous or compound heterozygous form with a more severe mutation), ppvB was 74%. In group C (P30L, V281L, P453S in homozygous or compound heterozygous form with a more severe mutation), ppvC was 64.7% to exhibit the nonclassical form of CAH, but 90% when excluding the P30L mutation. Thus, in general, a good genotype-phenotype relationship is shown in patients with either the severest or the mildest mutations. A considerable degree of divergence is observed within mutation groups of intermediate severity. As yet undefined factors modifying 21-hydroxylase gene expression and steroid hormone action are likely to account for these differences in phenotypic expression.

A Common Splice Site Mutation Is Shared by Two Families with Different Type 2N von Willebrand Disease Mutations

1999 ◽  
Vol 82 (09) ◽  
pp. 1061-1064 ◽  
Author(s):  
Kingsley Hampton ◽  
F. Eric Preston ◽  
Ian Peake ◽  
Anne Goodeve ◽  
I. Mandy Nesbitt
Keyword(s):  
Splice Site ◽  
Direct Sequencing ◽  
Splice Site Mutation ◽  
Von Willebrand Disease ◽  
The Other ◽  
Compound Heterozygous ◽  
Site Mutation ◽  
Disease Mutations ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryUsing an ELISA-based method to detect type 2N von Willebrand disease (VWD), we found two individuals with absent FVIII binding. Direct sequencing of the FVIII binding region of the von Willebrand factor (VWF) gene showed that one individual had an R854Q substitution whilst the other had a T791M substitution. The very low FVIII binding and the VWF:Ag levels in both individuals suggested a second defect on the other VWF allele. Conformation sensitive gel electrophoresis of polymerase chain reaction amplified DNA was used to detect an additional change in the VWF gene of each patient. Direct sequencing confirmed a previously unreported G to A transition in the donor splice site in intron 25 of both individuals which should result in a null allele. This was confirmed by mRNA analysis. These two individuals therefore have compound heterozygous VWD in which the only expressed allele has a type 2N mutation. In our population, such compound heterozygosity appears to be a significant cause of type 2N VWD.

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