scholarly journals Further Evidence of Mutational Heterogeneity of theXPCGene in Tunisian Families: A Spectrum of Private and Ethnic Specific Mutations

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Mariem Ben Rekaya ◽  
Manel Jerbi ◽  
Olfa Messaoud ◽  
Ahlem Sabrine Ben Brick ◽  
Mohamed Zghal ◽  
...  
Keyword(s):  
Molecular Diagnosis ◽  
Founder Effect ◽  
Xeroderma Pigmentosum ◽  
Direct Sequencing ◽  
Mutation Screening ◽  
Novel Mutations ◽  
Mutational Spectrum ◽  
Early Appearance ◽  
Southern Tunisia ◽  
Pathogenic Effect

Xeroderma Pigmentosum(XP) is a rare recessive autosomal cancer prone disease, characterized by UV hypersensitivity and early appearance of cutaneous and ocular malignancies. We investigated four unrelated patients suspected to be XP-C. To confirm linkage toXPCgene, genotyping and direct sequencing ofXPCgene were performed. Pathogenic effect of novel mutations was confirmed by reverse Transciptase PCR. Mutation screening revealed the presence of two novel mutations g.18246G>A and g.18810G>T in theXPCgene (NG_011763.1). The first is present in one patient XP50NEF, but the second is present in three unrelated patients (XP16KEB, XP28SFA, and XP45GB). These 3 patients are from three different cities of Southern Tunisia and bear the same haplotype, suggesting a founder effect. Reverse Transciptase PCR revealed the absence of theXPCmRNA. In Tunisia, as observed in an other severe genodermatosis, the mutational spectrum of XP-C group seems to be homogeneous with some clusters of heterogeneity that should be taken into account to improve molecular diagnosis of this disease.

scholarly journals Clinically-guided mutation screening of two families with hereditary retinal disease

2017 ◽  
Author(s):  
Jian Li ◽  
Aierken Yiming ◽  
Ping Wang
Keyword(s):  
Molecular Diagnosis ◽  
Large Scale ◽  
Direct Sequencing ◽  
Mutation Screening ◽  
Retinal Disease ◽  
Cost Effective ◽  
Mendelian Disease ◽  
Cost Effective Approach ◽  
Hereditary Retinal Disease ◽  
The Cost

AbstractHereditary retinal disease (HRD) is a series of Mendelian diseases affecting the retina in the eye. The genetic basis of HRD is very complicated, with more than 100 disease-causing genes being identified. Though NGS has allowed rapid and large-scale mutation screening of Mendelian disease, the cost of NGS still prevents its universal application all over the world, for an accurate molecular diagnosis. Here, by clinical guidance from patient phenotypes, we performed targeted molecular diagnosis by direct Sanger sequencing of the most likely candidate gene in two families diagnosed with HRD. Then we identified two novel protein-truncating variants in the gene CRB1. Our results demonstrated the notion that molecular diagnosis and clinical diagnosis can be mutually supplemented and clinically guided direct sequencing is a cost-effective approach for molecular diagnosis and subsequent genetic counseling.

scholarly journals Gene mapping in an anophthalmic pedigree of a consanguineous Pakistani family opened new horizons for research

2016 ◽  
Vol 19 (1) ◽  
pp. 77-84
Author(s):  
S Saleha ◽  
M Ajmal ◽  
S Zafar ◽  
A Hameed
Keyword(s):  
Linkage Mapping ◽  
Direct Sequencing ◽  
Mutation Screening ◽  
Ocular Tissue ◽  
Inherited Disease ◽  
Pakistani Family ◽  
New Horizons ◽  
Family Pedigree ◽  
Environmental Causes ◽  
Short Tandem

ABSTRACTClinical anophthalmia is a rare inherited disease of the eye and phenotype refers to the absence of ocular tissue in the orbit of eye. Patients may have unilateral or bilateral anophthalmia, and generally have short palpebral fissures and small orbits. Anophthalmia may be isolated or associated with a broader syndrome and may have genetic or environmental causes. However, genetic cause has been defined in only a small proportion of cases, therefore, a consanguineous Pakistani family of the Pashtoon ethnic group, with isolated clinical anophthalmia was investigated using linkage mapping. A family pedigree was created to trace the possible mode of inheritance of the disease. Blood samples were collected from affected as well as normal members of this family, and screened for disease-associated mutations. This family was analyzed for linkage to all the known loci of clinical anophthalmia, using microsatellite short tandem repeat (STR) markers. Direct sequencing was performed to find out disease-associated mutations in the candidate gene. This family with isolated clinical anophthalmia, was mapped to the SOX2 gene that is located at chromosome 3q26.3-q27. However, on exonic and regulatory regions mutation screening of the SOX2 gene, the disease-associated mutation was not identified. It showed that another gene responsible for development of the eye might be present at chromosome 3q26.3-q27 and needs to be identified and screened for the disease-associated mutation in this family.

Novel ABCD1 gene mutations in Iranian pedigrees with X-linked adrenoleukodystrophy

2019 ◽  
Vol 32 (11) ◽  
pp. 1207-1215
Author(s):  
Babak Emamalizadeh ◽  
Yousef Daneshmandpour ◽  
Abbas Tafakhori ◽  
Sakineh Ranji-Burachaloo ◽  
Sajad Shafiee ◽  
...  
Keyword(s):  
Protein Structure ◽  
Direct Sequencing ◽  
Gene Mutations ◽  
Protein Product ◽  
Structure And Function ◽  
Novel Mutations ◽  
Chain Reaction ◽  
Abcd1 Gene ◽  
Polymerase Chain ◽  
And Function

Abstract Background X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disorder, is caused by mutations in the ABCD1 gene located on Xq28. X-ALD is characterized by a spectrum of different manifestations varying in patients and families. Methods Four pedigrees with X-ALD consisting of patients and healthy members were selected for investigation of ABCD1 gene mutations. The mutation analysis was performed by polymerase chain reaction (PCR) followed by direct sequencing of all exons. The identified mutations were investigated using bioinformatics tools to predict their effects on the protein product and also to compare the mutated sequence with close species. Results One previously known missense mutation (c.1978 C > T) and three novel mutations (c.1797dupT, c.879delC, c.1218 C > G) were identified in the ABCD1 gene, each in one family. Predicting the effects of the mutations on protein structure and function indicated the probable damaging effect for them with significant alterations in the protein structure. We found three novel mutations in the ABCD1 gene with damaging effects on its protein product and responsible for X-ALD.

Mutation Screening of theHGDGene Identifies a Novel Alkaptonuria Mutation with Significant Founder Effect and High Prevalence

2014 ◽  
Vol 78 (3) ◽  
pp. 155-164 ◽  
Author(s):  
Srinivasan Sakthivel ◽  
Andrea Zatkova ◽  
Martina Nemethova ◽  
Milan Surovy ◽  
Ludevit Kadasi ◽  
...  
Keyword(s):  
Founder Effect ◽  
Mutation Screening ◽  
High Prevalence

scholarly journals Mutational spectrum of Mexican patients with tyrosinemia type 1: In silico modeling and predicted pathogenic effect of a novel missense FAH variant

2019 ◽  
Vol 7 (12) ◽  
Author(s):  
Isabel Ibarra‐González ◽  
Cynthia Fernández‐Lainez ◽  
Miguel Angel Alcántara‐Ortigoza ◽  
Ariadna González‐Del Angel ◽  
Liliana Fernández‐Henández ◽  
...  
Keyword(s):  
In Silico ◽  
Mutational Spectrum ◽  
Pathogenic Effect ◽  
In Silico Modeling ◽  
Tyrosinemia Type 1 ◽  
Mexican Patients

scholarly journals Novel mutations of RPGR in Chinese families with X-linked retinitis pigmentosa

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Zhimeng Zhang ◽  
Hehua Dai ◽  
Lei Wang ◽  
Tianchang Tao ◽  
Jing Xu ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Mutation Screening ◽  
Phenotype Correlation ◽  
Novel Mutations ◽  
Pathological Myopia ◽  
Nonsense Mutations ◽  
Chinese Families ◽  
Coding Regions ◽  
Genotype Phenotype Correlation ◽  
Male Patients

Abstract Background RP (retinitis pigmentosa) is a group of hereditary retinal degenerative diseases. XLRP is a relatively severe subtype of RP. Thus, it is necessary to identify genes and mutations in patients who present with X-linked retinitis pigmentosa. Methods Genomic DNA was extracted from peripheral blood. The coding regions and intron-exon boundaries of the retinitis pigmentosa GTPase regulator (RPGR) and RP2 genes were amplified by PCR and then sequenced directly. Ophthalmic examinations were performed to identify affected individuals from two families and to characterize the phenotype of the disease. Results Mutation screening demonstrated two novel nonsense mutations (c.1541C > G; p.S514X and c.2833G > T; p.E945X) in the RPGR gene. The clinical manifestation of family 1 with mutations in exon 13 was mild. Genotype-phenotype correlation analysis suggested that patients with mutations close to the downstream region of ORF15 in family 2 manifested an early loss of cone function. Family 2 carried a nonsense mutation in ORF15 that appeared to have a semi-dominant pattern of inheritance. All male patients and two female carriers in family 2 manifested pathological myopia (PM), indicating that there may be a distinctive X-linked genotype-phenotype correlation between RP and PM. Conclusions We identified two novel mutations of the RPGR gene, which broadens the spectrum of RPGR mutations and the phenotypic spectrum of the disease in Chinese families.

scholarly journals Five novel mutations located in exons III and IX of the protein C gene in patients presenting with defective protein C anticoagulant activity

Blood ◽  
1993 ◽  
Vol 82 (1) ◽  
pp. 159-168 ◽  
Author(s):  
S Gandrille ◽  
M Alhenc-Gelas ◽  
P Gaussem ◽  
MF Aillaud ◽  
E Dupuy ◽  
...  
Keyword(s):  
Amino Acids ◽  
Protein C ◽  
Denaturing Gradient Gel Electrophoresis ◽  
Anticoagulant Activity ◽  
Direct Sequencing ◽  
Catalytic Triad ◽  
Activity Levels ◽  
Novel Mutations ◽  
Protein C Deficiency

We describe five families presenting with type II hereditary protein C deficiency characterized by normal antigen and amidolytic activity levels but low anticoagulant activity. All the exons and intron/exon junctions of the protein C gene were studied using a strategy combining amplification by the polymerase chain reaction (PCR), denaturing gradient gel electrophoresis of the amplified fragments, and direct sequencing of fragments displaying altered melting behavior. We detected five novel mutations. Three were located in the C-terminal part of the propeptide encoded by exon III: Arginine (Arg)-5 to tryptophan (Trp), Arg-1 to histidine (His), and Arg-1 to cysteine (Cys) mutations. The two others, located in exon IX, affected Arg 229 and serine (Ser) 252, which were respectively replaced by glutamine (Gln) and asparagine (Asn). DNA studies of the other exons from affected individuals showed no other abnormalities. These novel mutations provide further insight into the importance of the affected amino acids located close to the active site, near Asp 257, one of the three amino acids of the catalytic triad. The low anticoagulant activity of the abnormal protein C indicated that Arg 229 and Ser 252 play a key role during the interaction between protein C and its cofactor protein S, phospholipids, or factors Va and VIIIa. The Arg-1 to Cys mutation led to the dimerization of protein C with another plasmatic component, as evidenced by the presence in the plasma of a high molecular weight form of protein C that disappeared after reduction. No molecular mass abnormalities were observed in heavy and light chains of all other protein C mutants. In the five families explored, 9 (64%) of the 14 subjects bearing the mutations reported thrombotic events. This suggests that the protein C amino acids affected by the mutations are very important for the in vivo expression of the antithrombotic properties of protein C.

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