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1.
J Appl Biomed ; 17(3): 184-189, 2019 Sep.
Article in English | MEDLINE | ID: mdl-34907700

ABSTRACT

Idiopathic scoliosis (IS) is a common medical condition in children, characterized by three-dimensional spinal curve and strong evidence of genetic predisposition. The purpose of the present case-control study is to examine the association between the polymorphic variant rs11190870 (T/C), near the LBX1 gene, and IS predisposition in distinct subgroups based on age at onset, family history and gender. A total of 127 IS patients and 254 unrelated controls of Southeastern European descent were recruited. The genotyping was carried out by TaqMan real-time amplification technology. The results were analyzed by the Pearson's Chi-squared Test and the Fisher's Exact Test with a value of p less than 0.05 as statistically significant. The T allele and homozygous TT genotype were associated with a greater incidence of IS. Our results suggest that there is a genetic association with IS in adolescents, familial and non-familial cases, and in females. Larger case-control studies are necessary to examine the genetic factors of IS/AIS etiology in infants, juveniles and males. In conclusion, the molecular genetic identification of diagnostic and prognostic molecular markers would make an early treatment including minimally invasive procedures possible.

2.
BMC Cancer ; 15: 523, 2015 Jul 17.
Article in English | MEDLINE | ID: mdl-26183948

ABSTRACT

BACKGROUND: About 3885 women are diagnosed with breast cancer and 1285 die from the disease each year in Bulgaria. However no genetic testing to identify the mutations in high-risk families has been provided so far. METHODS: We evaluated 200 Bulgarian women with primary invasive breast cancer and with personal/ family history of breast cancer for the presence of unequivocally damaging germline mutations in BRCA1/2 using Sanger sequencing. RESULTS: Of the 200 patients, 39 (19.5 %) carried a disease predisposing mutation, including 28 (14 %) with a BRCA1 mutation and 11 (5.5 %) with a BRCA2 mutation. At BRCA1, 6 different mutations were identified, including 2 frameshifts, 1 nonsense and 1 missense that had been previously reported (c.5030_5033delCTAA, c.5263_5264insC, c.4603G > T, c.181 T > G), and 2 frameshifts, which were novel to this study (c.464delA, c.5397_5403delCCCTTGG). At BRCA2, 7 different frameshift mutations were identified, including 5 previously reported (5851_5854delAGTT, c.5946delT, c.5718_5719delCT, c.7910_7914delCCTTT,c.9098_9099insA) and 2 novel (c.8532_8533delAA, c.9682delA). A BRCA1 mutation was found in 18.4 % of women diagnosed with breast cancer at/or under the age of 40 compared to 11.2 % of women diagnosed at a later age; a BRCA2 mutation was found in 4 % of women diagnosed at/or under the age of 40 compared to 6.5 % of women diagnosed at a later age. A mutation was present in 26.8 % patients with a positive family history and in 14.4 % of women with a negative family history. The most prevalent mutation observed in 22 patients (11 %) was BRCA1 c.5263_5264insC, a known Slavic mutation with founder effect in Eastern European and AJ communities. Other recurrent mutations were BRCA2 c.9098-9099insA (2 %), BRCA1 c.181T > G (1 %) and BRCA2 c.5851_5854delAGTT (1 %). Notably, BRCA1 c.5263_5264insC represented 56 % of all mutations identified in this series. Of the 22 patients with BRCA1 c.5263_5264insC, 9 were diagnosed with early onset breast cancer, 11 with TNBCs, 4 with bilateral breast cancer, and 6 with both breast and ovarian cancer. CONCLUSIONS: This is the first comprehensive study of the BRCA1/2 mutation spectrum in Bulgaria and will assist the establishment of efficient protocols for genetic testing and individualized risk assessment for Bulgarian breast/ovarian cancer patients and healthy individuals at a high-risk.


Subject(s)
BRCA1 Protein/genetics , BRCA2 Protein/genetics , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Mutation , Adult , Aged , Breast Neoplasms/ethnology , Bulgaria/ethnology , Female , Founder Effect , Genetic Predisposition to Disease , High-Throughput Nucleotide Sequencing , Humans , Middle Aged , Precision Medicine , Sequence Analysis, DNA
3.
Nat Genet ; 38(2): 197-202, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16429158

ABSTRACT

Charcot-Marie-Tooth (CMT) neuropathies are common disorders of the peripheral nervous system caused by demyelination or axonal degeneration, or a combination of both features. We previously assigned the locus for autosomal dominant intermediate CMT neuropathy type C (DI-CMTC) to chromosome 1p34-p35. Here we identify two heterozygous missense mutations (G41R and E196K) and one de novo deletion (153-156delVKQV) in tyrosyl-tRNA synthetase (YARS) in three unrelated families affected with DI-CMTC. Biochemical experiments and genetic complementation in yeast show partial loss of aminoacylation activity of the mutant proteins, and mutations in YARS, or in its yeast ortholog TYS1, reduce yeast growth. YARS localizes to axonal termini in differentiating primary motor neuron and neuroblastoma cultures. This specific distribution is significantly reduced in cells expressing mutant YARS proteins. YARS is the second aminoacyl-tRNA synthetase found to be involved in CMT, thereby linking protein-synthesizing complexes with neurodegeneration.


Subject(s)
Axons/enzymology , Charcot-Marie-Tooth Disease/enzymology , Charcot-Marie-Tooth Disease/genetics , Genes, Dominant/genetics , Mutation/genetics , Tyrosine-tRNA Ligase/genetics , Tyrosine-tRNA Ligase/metabolism , Amino Acid Sequence , Animals , Axons/metabolism , Axons/pathology , Biological Assay , COS Cells , Cell Line, Tumor , Cells, Cultured , Charcot-Marie-Tooth Disease/metabolism , Chlorocebus aethiops , Genetic Complementation Test , Heterozygote , Humans , Mice , Molecular Sequence Data , Protein Transport , Recombinant Proteins , Saccharomyces cerevisiae/cytology , Saccharomyces cerevisiae/growth & development , Sequence Alignment , Tyrosine-tRNA Ligase/chemistry
4.
Mol Genet Metab ; 113(1-2): 76-83, 2014.
Article in English | MEDLINE | ID: mdl-25087164

ABSTRACT

Investigation of 31 of Roma patients with congenital lactic acidosis (CLA) from Bulgaria identified homozygosity for the R446* mutation in the PDHX gene as the most common cause of the disorder in this ethnic group. It accounted for around 60% of patients in the study and over 25% of all CLA cases referred to the National Genetic Laboratory in Bulgaria. The detection of a homozygous patient from Hungary and carriers among population controls from Romania and Slovakia suggests a wide spread of the mutation in the European Roma population. The clinical phenotype of the twenty R446* homozygotes was relatively homogeneous, with lactic acidosis crisis in the first days or months of life as the most common initial presentation (15/20 patients) and delayed psychomotor development and/or seizures in infancy as the leading manifestations in a smaller group (5/20 patients). The subsequent clinical picture was dominated by impaired physical growth and a very consistent pattern of static cerebral palsy-like encephalopathy with spasticity and severe to profound mental retardation seen in over 80% of cases. Most patients had a positive family history. We propose testing for the R446* mutation in PDHX as a rapid first screening in Roma infants with metabolic acidosis. It will facilitate and accelerate diagnosis in a large proportion of cases, allow early rehabilitation to alleviate the chronic clinical course, and prevent further affected births in high-risk families.


Subject(s)
Acidosis, Lactic/genetics , Founder Effect , Mutation , Pyruvate Dehydrogenase Complex/genetics , Acidosis, Lactic/diagnosis , Adolescent , Child , Child, Preschool , Codon , Consanguinity , DNA Mutational Analysis , Female , Genotype , Humans , Infant , Infant, Newborn , Male , Phenotype , Romania , Slovakia
5.
Nat Genet ; 35(2): 185-9, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14517542

ABSTRACT

Congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome (OMIM 604168) is an autosomal recessive developmental disorder that occurs in an endogamous group of Vlax Roma (Gypsies; refs. 1-3). We previously localized the gene associated with CCFDN to 18qter, where a conserved haplotype suggested a single founder mutation. In this study, we used recombination mapping to refine the gene position to a 155-kb critical interval. During haplotype analysis, we found that the non-transmitted chromosomes of some unaffected parents carried the conserved haplotype associated with the disease. Assuming such parents to be completely homozygous across the critical interval except with respect to the disease-causing mutation, we developed a new 'not quite identical by descent' (NQIBD) approach, which allowed us to identify the mutation causing the disease by sequencing DNA from a single unaffected homozygous parent. We show that CCFDN is caused by a single-nucleotide substitution in an antisense Alu element in intron 6 of CTDP1 (encoding the protein phosphatase FCP1, an essential component of the eukaryotic transcription machinery), resulting in a rare mechanism of aberrant splicing and an Alu insertion in the processed mRNA. CCFDN thus joins the group of 'transcription syndromes' and is the first 'purely' transcriptional defect identified that affects polymerase II-mediated gene expression.


Subject(s)
Cataract/genetics , Chromosomes, Human, Pair 18 , Face/abnormalities , Nervous System Diseases/genetics , Phosphoprotein Phosphatases/genetics , RNA Polymerase II/genetics , Amino Acid Sequence , Base Sequence , Binding Sites , Cataract/congenital , Chromosome Mapping , Conserved Sequence , Genes, Recessive , Humans , Introns , Molecular Sequence Data , Phosphoprotein Phosphatases/metabolism , Point Mutation , Polymerase Chain Reaction , RNA Polymerase II/chemistry , RNA Polymerase II/metabolism , Roma/genetics , Syndrome
6.
Nat Genet ; 36(6): 597-601, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15122253

ABSTRACT

Distal hereditary motor neuropathies are pure motor disorders of the peripheral nervous system resulting in severe atrophy and wasting of distal limb muscles. In two pedigrees with distal hereditary motor neuropathy type II linked to chromosome 12q24.3, we identified the same mutation (K141N) in small heat-shock 22-kDa protein 8 (encoded by HSPB8; also called HSP22). We found a second mutation (K141E) in two smaller families. Both mutations target the same amino acid, which is essential to the structural and functional integrity of the small heat-shock protein alphaA-crystallin. This positively charged residue, when mutated in other small heat-shock proteins, results in various human disorders. Coimmunoprecipitation experiments showed greater binding of both HSPB8 mutants to the interacting partner HSPB1. Expression of mutant HSPB8 in cultured cells promoted formation of intracellular aggregates. Our findings provide further evidence that mutations in heat-shock proteins have an important role in neurodegenerative disorders.


Subject(s)
Charcot-Marie-Tooth Disease/genetics , Heat-Shock Proteins/genetics , Point Mutation , Protein Serine-Threonine Kinases , Amino Acid Sequence , Animals , COS Cells , Cell Line , Charcot-Marie-Tooth Disease/metabolism , Female , Heat-Shock Proteins/chemistry , Heat-Shock Proteins/metabolism , Humans , Male , Molecular Chaperones , Molecular Sequence Data , Pedigree , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Sequence Homology, Amino Acid , Transfection
8.
J Clin Neurophysiol ; 39(6): 510-512, 2022 Sep 01.
Article in English | MEDLINE | ID: mdl-33181595

ABSTRACT

INTRODUCTION: Wilson disease (WD) is an inherited disorder of copper metabolism presenting with a variety of symptoms but commonly as a liver or neuropsychiatric disease. Abnormal evoked responses are constantly found among patients with neurologic manifestations and sometimes in patients with hepatic presentation or in presymptomatic siblings. The aim of our study was to assess visual and brainstem auditory evoked potentials (BAEP) in patients with various presentation of WD. METHODS: Visual evoked potentials (VEP) were performed in 36 WD patients and BAEP were done in 37 WD patients. RESULTS: Brainstem auditory evoked potentials were normal in patients with isolated hepatic presentation, whereas they were abnormal in 93.5% of patients with neurologic symptoms. There was significant prolongation of the latencies of the III and V waves and of the interpeak III-V and I-V latencies in comparison with the healthy controls (T-test P = 0). Abnormal VEP were observed in 81% of the patients including six of seven neurologically asymptomatic patients. The values of N75, P100, and N145 latencies were significantly longer in all patients than in healthy controls (T-test). CONCLUSIONS: The data showed that VEP and BAEP are more frequently abnormal in WD than previously reported. The abnormal VEP and BAEP even without clinical signs and brain MRI abnormalities point to subclinical involvement of visual and auditory pathways caused by copper toxicity. Because VEP and BAEP are noninvasive and widely available, they should be performed in all patents with WD.


Subject(s)
Evoked Potentials, Visual , Hepatolenticular Degeneration , Copper , Evoked Potentials , Evoked Potentials, Auditory , Evoked Potentials, Auditory, Brain Stem/physiology , Humans , Neurologic Examination
9.
J Inherit Metab Dis ; 34(4): 917-21, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21499719

ABSTRACT

EXT1/EXT2-CDG (Multiple cartilagineous exostoses, hereditary multiple osteochondroma (MO); OMIM 133700/133701) are common defects of O-xylosylglycan glycosylation. The diagnostic criteria are at least two osteochondromas of the juxta-epiphyseal region of long bones with in the majority of cases a positive family history and/or mutation in one of the EXT genes. The authors report data on clinical symptoms and complications of 23 patients (from 16 families), discussing the family history, age of diagnosis, new clinical and molecular data. Fifteen mutations and large deletions, of which nine are new, were detected in the EXT1 and EXT2 gene by sequence analysis, FISH and MLPA analysis.


Subject(s)
Exostoses, Multiple Hereditary/genetics , N-Acetylglucosaminyltransferases/genetics , Adolescent , Adult , Bulgaria , Child , Child, Preschool , Congenital Disorders of Glycosylation/complications , Congenital Disorders of Glycosylation/genetics , DNA Mutational Analysis/methods , Exostoses, Multiple Hereditary/complications , Exostoses, Multiple Hereditary/diagnosis , Female , Genetic Predisposition to Disease/genetics , Humans , Male , Middle Aged , N-Acetylglucosaminyltransferases/physiology , Young Adult
10.
Neuromuscul Disord ; 18(8): 667-70, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18653336

ABSTRACT

Duchenne/Becker muscular dystrophy (DMD/BMD), the most common X-linked muscular dystrophy is caused by mutations in the enormously large DMD gene, encoding the protein called dystrophin. This gene was screened in a group of 27 unrelated Bulgarian DMD/BMD patients by MLPA analysis/complete sequencing. We managed to clarify the disease-causing mutation in 96.3% of the analyzed families. The MLPA analysis revealed 17 deletions (including a deletion of the very last exon 79), 6 duplications and 1 point mutation. Two additional point mutations (one of them novel) were detected after complete sequencing of the DMD gene. Altogether, 25 carriers and 11 noncarriers were detected in our families. The MLPA test proved to be a powerful tool in detecting deletions/duplications and in some cases point mutations/polymorphisms along the DMD gene. Using this approach in combination with a direct gene sequencing a number of Bulgarian DMD/BMD patients are genetically clarified and prepared for gene therapy in future.


Subject(s)
Dystrophin/genetics , Muscular Dystrophy, Duchenne/genetics , Bulgaria/epidemiology , Electrophoresis, Capillary , Exons/genetics , Female , Gene Deletion , Gene Frequency , Heterozygote , Humans , Infant , Male , Muscular Dystrophy, Duchenne/epidemiology , Mutation/genetics , Mutation/physiology , Nucleic Acid Amplification Techniques , Phenotype
11.
Am J Med Genet A ; 146A(13): 1736-40, 2008 Jul 01.
Article in English | MEDLINE | ID: mdl-18546276

ABSTRACT

The patient is a 24-year-old woman who first came for consultation at age 10 years. Based on clinical phenotype and thin-layer chromatography of urinary oligosaccharides, peripheral leukocytes were sent for beta-galactosidase assay. This testing showed a deficiency in enzyme activity, and gene mutation analysis identified a previously reported mutation p.H281Y (875C > T) and a novel mutation p.W273R (817T > C). Unlike previously reported patients, mutant enzymes in this patient's cultured skin fibroblasts did not respond to treatment with a chaperone compound, N-octyl-4-epi-beta-valienamine.


Subject(s)
Mucopolysaccharidosis IV/enzymology , Mucopolysaccharidosis IV/genetics , beta-Galactosidase/deficiency , beta-Galactosidase/genetics , Adult , Amino Acid Substitution , Female , Fibroblasts/drug effects , Fibroblasts/enzymology , Hexosamines/pharmacology , Humans , In Vitro Techniques , Mucopolysaccharidosis IV/pathology , Phenotype , Point Mutation , Skin/drug effects , Skin/enzymology
12.
Brain ; 130(Pt 4): 1050-61, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17360762

ABSTRACT

Niemann-Pick disease (NPD), an autosomal recessive disorder resulting from mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene, is subdivided into the acute, lethal neuronopathic type A, and the chronic visceral type B, explained by the different residual activity levels of acid sphingomyelinase (ASMase). An increasing number of reports on intermediate forms, challenging this traditional clinical classification, have described a broad range of neurological manifestations; however genotype-phenotype correlations have been compromised by relatively small sample sizes and/or allelic heterogeneity. Here we present a genetically homogeneous group of 20 Gypsy patients with intermediate NPD, where we observed a surprising diversity of neurological features. All affected subjects were homozygous for the same ancestral mutation, W391G in SMPD1, yet displayed the entire spectrum of phenotypic variation observed previously in unrelated affected subjects of diverse ethnicity and disease-causing mutations, ranging from subclinical retinal involvement to severe ataxia, cognitive deficits and psychiatric disorders. The clinical heterogeneity of W391G homozygotes points to additional factors, beyond SMPD1 and residual ASMase, which determine the localization, extent and severity of neural involvement. The phenotype similarity of affected relatives suggests a possible role of genetic modifying factors. In practical terms, W391 is common in the Gypsy population and the diagnosis of NPD should be borne in mind despite the atypical course of the disease. Generally, our findings indicate that mutation analysis is of limited value in predicting brain damage, and the option of enzyme replacement therapy should be considered in intermediate NPD.


Subject(s)
Central Nervous System Diseases/genetics , Niemann-Pick Diseases/genetics , Sphingomyelin Phosphodiesterase/deficiency , Adolescent , Adult , Age of Onset , Base Sequence , Central Nervous System Diseases/complications , Central Nervous System Diseases/ethnology , Child , Child, Preschool , Cognition Disorders/complications , Cognition Disorders/ethnology , Cognition Disorders/genetics , Electroencephalography/methods , Family Health , Female , Fluorescein Angiography/methods , Genotype , Humans , Infant , Macula Lutea/pathology , Male , Mental Disorders/complications , Mental Disorders/ethnology , Mental Disorders/genetics , Mutation , Niemann-Pick Diseases/complications , Niemann-Pick Diseases/ethnology , Peripheral Nervous System Diseases/complications , Peripheral Nervous System Diseases/ethnology , Peripheral Nervous System Diseases/genetics , Phenotype , Sphingomyelin Phosphodiesterase/genetics
13.
Case Rep Genet ; 2018: 3028145, 2018.
Article in English | MEDLINE | ID: mdl-30147969

ABSTRACT

Congenital muscle dystrophies (CMD) are genetically and clinically heterogeneous hereditary myopathies mainly with autosomal recessive type of inheritance. The most common form worldwide is considered to be merosin-deficient muscle dystrophy type 1A, called MDC1A (due to laminin-α2 defects as a result of LAMA2 gene mutation), accounting for 30-40% of total cases of CMD. The exact molecular and clinical diagnoses, respectively, are a prerequisite for the most effective treatment; sometimes orphan drugs exist for some rare diseases. One of such drugs is Tarix, which was FDA approved and announced in 2016 for treatment of MDC1A. Here we present a patient diagnosed postmortem as having early-onset LAMA2-related muscular dystrophy as a result of mutations in LAMA2, identified by Sanger sequencing in his parents: a novel nonsense mutation c.4452T>A in exon 31, identified in the mother, and a known pathogenic nonsense mutation c.2901C>A in exon 21, detected in the father. The truncating nature of both nonsense mutations made the clinical presentation severe and the outcome fatal. Genetic analysis in such cases of muscle dystrophy is of utmost impact, because it makes the correct diagnosis with at least some specific options for treatment, makes the prognosis depending on the severity of mutation discovered, determines reproductive risk, and offers prophylaxis in the family by means of prenatal or preimplantation diagnostics.

14.
Anal Cell Pathol (Amst) ; 2018: 6836092, 2018.
Article in English | MEDLINE | ID: mdl-30079294

ABSTRACT

Idiopathic scoliosis (IS) is a common medical condition beginning in childhood and characterized by strong evidence for a genetic susceptibility to three-dimensional spinal deformity. The primary goal of the current case-control study is to examine the association between the TGFB1 (-509C/T) functional polymorphic variant and genetic predisposition to IS in the Bulgarian population and the genotype-phenotype correlations in distinct case-control subgroups based on age at onset, family history, and gender. A total of 127 patients with primary scoliosis and 254 gender-matched control subjects were recruited. The mean Cobb angle was 53.8 ± 21.2°. Genotyping of cases and controls was performed using the TaqMan real-time amplification technique. The results were processed statistically using Pearson's Chi-squared test and Fisher's exact test with a value of p less than 0.05 as statistically significant. The polymorphic T allele and TT genotype were associated with a greater incidence of IS and can be considered as predisposing factors with a moderate effect on deformity development. The current results suggested that there was a genetic predisposition in early and late onset IS and familial, sporadic, and female cases. Nevertheless, replication studies are needed to reveal the relationship between the TGFB1 locus and certain subtypes of IS in different populations.


Subject(s)
Scoliosis/genetics , Transforming Growth Factor beta1/genetics , Adolescent , Alleles , Bulgaria , Case-Control Studies , Chi-Square Distribution , Child , Child, Preschool , Female , Gene Frequency/genetics , Genetic Association Studies , Genetic Predisposition to Disease/genetics , Genotype , Humans , Infant , Infant, Newborn , Male , Polymorphism, Single Nucleotide/genetics
15.
Arch Neurol ; 64(5): 706-13, 2007 May.
Article in English | MEDLINE | ID: mdl-17502470

ABSTRACT

OBJECTIVE: To study the frequency and distribution of mutations in SPG3A in a large cohort of patients with hereditary spastic paraplegia. DESIGN: We screened a large cohort of 182 families and isolated cases with pure or complex hereditary spastic paraplegia phenotypes, which were negative for mutations in SPG4. RESULTS: In 12 probands (6.6%), we identified 12 different SPG3A mutations (11 missense and 1 insertion/frameshift) of which 7 were novel and 3 were de novo. We found incomplete penetrance in 1 family (G482V). In most cases, SPG3A mutations were associated with an early age at onset (mean, 3 y); however, in 1 family (R495W mutation), symptoms started later (mean, 14 y) with clear intrafamilial variability (8-28 y). Six patients with an SPG3A mutation (F151S, Q191R, M408T, G469A, R495W) originating from 5 unrelated families presented with a complex form of hereditary spastic paraplegia associated with a neuropathy (17%). Our electrophysiological and pathological findings confirmed an axonal sensory-motor neuropathy. There was no correlation between the genotype and the presence of a neuropathy. CONCLUSIONS: We conclude that mutations in SPG3A represent an important cause of patients in the overall hereditary spastic paraplegia population. SPG3A is more often associated with a neuropathy than previously assumed. Therefore, patients with a bipyramidal syndrome and a neuropathy should be screened for mutations in SPG3A.


Subject(s)
Genetic Predisposition to Disease , Membrane Proteins/genetics , Mutation , Polyneuropathies/genetics , Spastic Paraplegia, Hereditary/genetics , Vesicular Transport Proteins/genetics , Adolescent , Adult , Age of Onset , Aged , Amides , Aminobutyrates , Butyrates , Child , Cohort Studies , DNA Mutational Analysis , Family Health , Female , Humans , Male , Middle Aged , Polyneuropathies/complications , Polyneuropathies/pathology , Spastic Paraplegia, Hereditary/complications , Spastic Paraplegia, Hereditary/pathology
16.
Eur J Med Genet ; 60(6): 321-325, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28392475

ABSTRACT

Renal cysts are common malformation during the prenatal and postnatal period and frequent cause of chronic kidney or ESRD. More than 70 genes have been shown to play role in their pathology. Part of them are responsible for the structure and function of the cilia, which assigns a large proportion of the renal cystic diseases in the ciliopathies. Another group of genes responsible for cystic kidneys encodes transcription factors with crucial role during organogenesis. We describe here a systematic approach for identifying the genetic cause(s) of an unusually severe form of renal cystic disease in a family with multiple affected siblings. High throughput mutations screening of the parents and one of the children was applied for identifying the genetic causes of the disease. The affected child was found to have inherited 3 deleterious mutations in two nephronophthisis genes, NPHP3 and NPHP4. The possibility for epistatic interaction of the NPHP mutations as well as the modifying effect of other inherited genetic variants is discussed.


Subject(s)
Kidney Diseases, Cystic/genetics , Kinesins/genetics , Proteins/genetics , Adult , Child , Epistasis, Genetic , Female , Genes, Modifier , Humans , Infant, Newborn , Kidney Diseases, Cystic/diagnosis , Male , Mutation , Pedigree
17.
Mol Vis ; 12: 909-14, 2006 Aug 11.
Article in English | MEDLINE | ID: mdl-16917484

ABSTRACT

PURPOSE: To identify the disease-causing mutations in two large Bulgarian Romani (Gypsy) pedigrees: one with autosomal dominant retinitis pigmentosa (adRP) with partial penetrance and the other with severe X-linked RP (xlRP). METHODS: Detailed clinical investigations were undertaken and genomic DNA was extracted from blood samples. DNA was analyzed by PCR amplification with gene-specific primers and direct genomic sequencing. RESULTS: Analysis of the complete coding sequence of PRPF31 in the adRP family led to the identification of a new heterozygous splice site mutation IVS6+1G>T. RPGR mutation screening in affected male individuals in the X-linked RP family identified a hemizygous c.ORF15+652_653delAG mutation. Interestingly this mutation was found in a homozygous state in one severely affected female from the family. CONCLUSIONS: In this first report of molecular genetic analysis of retinitis pigmentosa in Romani families, we describe a novel PRPF31 mutation and present the first case of a homozygous mutation in the RPGR gene in a female individual.


Subject(s)
Eye Proteins/genetics , Molecular Biology , Mutation , Retinitis Pigmentosa/genetics , Roma/genetics , Adolescent , Adult , Base Sequence , Chromosomes, Human, X , Female , Genes, Dominant , Genetic Linkage , Guanine , Homozygote , Humans , Introns , Male , Middle Aged , Molecular Sequence Data , Pedigree , Penetrance , Thymine
18.
World J Gastroenterol ; 12(48): 7848-51, 2006 Dec 28.
Article in English | MEDLINE | ID: mdl-17203532

ABSTRACT

AIM: To present novel frameshift mutation c.31delC [p.L11X] in the MLH1 gene identified in an extended Bulgarian hereditary non-polyposis colorectal cancer (HNPCC) family and to analyze the molecular and clinical findings within the pedigree concerning the proposal of adequate individual prophylactic strategy for all mutation carriers. METHODS: The pedigree of the family consists of 42 members in four generations. Search for mutations in the MLH1 and hMSH2 genes was performed in the proband. After PCR amplification of all exons including flanking intronic regions, amplicons were directly sequenced. RESULTS: The mutation was found in nine from the thirteen pedigree members who signed informed consent to participate in the study. In three adenocarcinomas, microsatellite instability and lack of the MLH1 protein expression were detected. The only one tubulovillous adenoma analyzed was microsatellite stable and the MLH1 protein showed an intact staining. CONCLUSION: The newly described mutation c.31delC is HNPCC causative. Besides the typical clinical features of the syndrome, we found a specific pathologic manifestation such as moderate to high differentiated adenocarcinomas of the colon. One of the mutation carriers developed a benign giant cell soft tissue tumor. The primary tumor localizations were frequently extracolonic and detailed yearly gastrointestinal and gynecological examinations have been proposed to the mutation carriers. We emphasize the importance of including the HNPCC genetic counseling and testing as well in the following surveillance of all patients at risk in the services covered by the health insurance in Bulgaria.


Subject(s)
Adenocarcinoma/genetics , Carrier Proteins/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Frameshift Mutation/genetics , Nuclear Proteins/genetics , Pedigree , Adaptor Proteins, Signal Transducing , Adult , Aged , Aged, 80 and over , Bulgaria , DNA, Neoplasm/genetics , Female , Gene Expression Regulation, Neoplastic , Genetic Counseling , Humans , Male , Microsatellite Instability , Middle Aged , MutL Protein Homolog 1 , MutS Homolog 2 Protein/genetics , Sequence Deletion/genetics
19.
J Biomark ; 2016: 5318239, 2016.
Article in English | MEDLINE | ID: mdl-27293961

ABSTRACT

The concept of disease-modifier genes as an element of genetic heterogeneity has been widely accepted and reported. The aim of the current study is to investigate the association between the promoter polymorphism TPH1 (rs10488682) and progression of idiopathic scoliosis (IS) in Eastern European population sample. A total of 105 patients and 210 healthy gender-matched controls were enrolled in this study. The TPH1 promoter polymorphism was genotyped by amplification followed by restriction. The statistical analysis was performed by Fisher's Exact Test. The results indicated that the genotypes and alleles of TPH1 (rs10488682) are not correlated with curve severity, curve pattern, or bracing. Therefore, the examined polymorphic variant could not be considered as a genetic factor with modifying effect of IS. In conclusion, this case-control study revealed no statistically significant association between TPH1 (rs10488682) and progression of IS in Eastern European population sample. These preliminary results should be replicated in extended population studies including larger sample sizes. The identification of molecular markers for IS could be useful for a more accurate prognosis of the risk for a rapid progression of the curve. That would permit early stage treatment of the patient with the least invasive procedures.

20.
Spine (Phila Pa 1976) ; 41(9): 785-91, 2016 May.
Article in English | MEDLINE | ID: mdl-26656061

ABSTRACT

STUDY DESIGN: A case-control study was performed on 105 patients with idiopathic scoliosis (IS) and 210 unrelated gender-matched controls from Bulgarian population. OBJECTIVE: Investigation of the association between common genetic polymorphisms of IL-6 and MMP3 genes and the etiology and progression of IS among Bulgarian patients. SUMMARY OF BACKGROUND DATA: The IL-6 and MMP3 genes have been considered as candidate genes of IS in Caucasian population. METHODS: Molecular detection of the promoter polymorphisms of IL-6 and MMP3 was performed by polymerase chain reaction followed by restriction fragment length polymorphism. The statistical analysis was performed by χ test with a value of P < 0.05 as statistically significant. The combinatorial effect of the candidate genes was also examined. RESULTS: This case-control study revealed statistically significant association between the IL-6 (rs1800795) functional polymorphism and susceptibility to IS (χ = 16.055; P < 0.0001). In addition, a significant association between IL-6 (rs1800795) and curve severity was detected (χ = 16.87; P < 0.0001). No genotype or allele of MMP3 (rs3025058) was found to be correlated to the onset or progression of IS (P > 0.05). One IL-6-MMP3 genotype combination was associated with the susceptibility to IS. CONCLUSION: IL-6 gene could be considered as a susceptibility and modifying factor of IS. The identification of molecular markers with diagnostic and prognostic value could be useful for early detection of children at risk for the development of IS and for prognosis of the risk for a rapid deformity progression. That would facilitate the therapy decisions and early stage treatment of the patient with the least invasive procedures. LEVEL OF EVIDENCE: 4.


Subject(s)
Genetic Association Studies/methods , Interleukin-6/genetics , Matrix Metalloproteinase 3/genetics , Polymorphism, Single Nucleotide/genetics , Scoliosis/diagnosis , Scoliosis/genetics , Adolescent , Bulgaria/epidemiology , Case-Control Studies , Child , Child, Preschool , Female , Genetic Markers/genetics , Humans , Male , Scoliosis/epidemiology
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