ABSTRACT
Aromatic amino acid decarboxylase (AADC) deficiency is a rare monogenic disease, often fatal in the first decade, causing severe intellectual disability, movement disorders and autonomic dysfunction. It is due to mutations in the gene coding for the AADC enzyme responsible for the synthesis of dopamine and serotonin. Using whole exome sequencing, we have identified a novel homozygous c.989C > T (p.Pro330Leu) variant of AADC causing AADC deficiency. Pro330 is part of an essential structural and functional element: the flexible catalytic loop suggested to cover the active site as a lid and properly position the catalytic residues. Our investigations provide evidence that Pro330 concurs in the achievement of an optimal catalytic competence. Through a combination of bioinformatic approaches, dynamic light scattering measurements, limited proteolysis experiments, spectroscopic and in solution analyses, we demonstrate that the substitution of Pro330 with Leu, although not determining gross conformational changes, results in an enzymatic species that is highly affected in catalysis with a decarboxylase catalytic efficiency decreased by 674- and 194-fold for the two aromatic substrates. This defect does not lead to active site structural disassembling, nor to the inability to bind the pyridoxal 5'-phosphate (PLP) cofactor. The molecular basis for the pathogenic effect of this variant is rather due to a mispositioning of the catalytically competent external aldimine intermediate, as corroborated by spectroscopic analyses and pH dependence of the kinetic parameters. Altogether, we determined the structural basis for the severity of the manifestation of AADC deficiency in this patient and discussed the rationale for a precision therapy.
Subject(s)
Amino Acid Metabolism, Inborn Errors , Aromatic-L-Amino-Acid Decarboxylases , Amino Acid Metabolism, Inborn Errors/genetics , Amino Acid Metabolism, Inborn Errors/metabolism , Aromatic-L-Amino-Acid Decarboxylases/deficiency , Aromatic-L-Amino-Acid Decarboxylases/genetics , Aromatic-L-Amino-Acid Decarboxylases/metabolism , Catalysis , Dopamine/metabolism , HumansABSTRACT
Loricrin keratoderma (LK) is a rare autosomal dominant genodermatosis caused by LORICRIN gene mutations. The pathogenesis of the disease is not yet fully understood. So far, only 10 pathogenic variants in LORICRIN have been described, with all of them but one being deletions or insertions. The significance of rare nonsense variants remains unclear. Furthermore, no data regarding the RNA expression in affected patients are available. The aim of this study is to describe the two variants in the LORICRIN gene found in two distinct families: the novel pathogenic variant c.639_642dup and a rare c.10C > T (p.Gln4Ter) of unknown significance. We also present the results of the transcriptome analysis of the lesional loricrin keratoderma epidermis of a patient with c.639_642dup. We show that in the LK lesion, the genes associated with epidermis development and keratocyte differentiation are upregulated, while genes engaged in cell adhesion, differentiation developmental processes, ion homeostasis and transport, signaling and cell communication are downregulated. In the context of the p.Gln4Ter clinical significance evaluation, we provide data indicating that LORICRIN haploinsufficiency has no skin consequences. Our results give further insight into the pathogenesis of LK, which may have therapeutic implications in the future and important significance in the context of genetic counseling.
Subject(s)
Skin Diseases, Genetic , Humans , Skin Diseases, Genetic/metabolism , Epidermis/metabolism , Gene Expression ProfilingABSTRACT
PURPOSE: Loss of function variants of the transient receptor potential cation channel, subfamily V, member 6 (TRPV6) have been recently associated with chronic pancreatitis (CP) in Japanese, German and French patients. Here, we investigated the association of TRPV6 variants with CP in independent European cohorts of early-onset CP patients from Poland and Germany. PATIENTS AND METHODS: We enrolled 152 pediatric CP patients (median age 8.6 yrs) with no history of alcohol/smoking abuse and 472 controls from Poland as well as 157 nonalcoholic young CP patients (median age 20 yrs) and 750 controls from Germany. Coding regions of TRPV6 were screened by Sanger and next generation sequencing. Selected, potentially pathogenic TRPV6 variants were expressed in HEK293T cells and TRPV6 activity was analyzed using ratiometric Ca2+ measurements. RESULTS: Overall, we identified 10 novel (3 nonsense and 7 missenses) TRPV6 variants in CP patients. TRPV6 p.V239SfsX53 nonsense variant and the variants showing significant decrease in intracellular Ca2+ concentration in HEK293T cells (p.R174X, p.L576R, p.R342Q), were significantly overrepresented in Polish patients as compared to controls (6/152, 3.9% vs. 0/358, 0%; P = 0,0007). Nonsense TRPV6 variants predicted as loss of function (p.V239SfsX53 and p.R624X) were also significantly overrepresented in German patients (3/157; 2.0% vs 0/750; 0%, P = 0.005). CONCLUSIONS: We showed that TRPV6 loss of function variants are associated with elevated CP risk in early-onset Polish and German patients confirming that TRPV6 is a novel CP susceptibility gene.
Subject(s)
Pancreatitis, Chronic , Adult , Calcium Channels/genetics , Child , Germany/epidemiology , HEK293 Cells , Humans , Pancreatitis, Chronic/genetics , Poland/epidemiology , TRPV Cation Channels/genetics , Young AdultABSTRACT
Ectodermal dysplasias are a wide group of genetic disorders characterised by clinical symptoms in ectodermal derivatives (most frequently teeth, hair, nails and sweat glands). There is a number of genes, which, if mutated, can cause the specified phenotype. The molecular basis of many ectodermal dysplasias have been investigated. The phenotype often results from the imparied communication in molecular pathways important in embryonic morphogenesis or disturbed function of protein complexes involved in homeostasis, adhesion and stability of the cells in the tissue. Different classification systems have been proposed to group ectodermal dysplasias according to clinical symptoms or molecular basis. Molecular technologies have let recently to expand diagnostic abilities for ectodermal dysplasias patients. Certainly in the nearest years new genes and mutations will be discovered as a cause of ectodermal dysplasias.
Subject(s)
Ectodermal Dysplasia , Ectodermal Dysplasia/diagnosis , Ectodermal Dysplasia/genetics , Humans , Mutation , PhenotypeABSTRACT
INTRODUCTION: Epidermolysis bullosa (EB) is a rare genetic skin disorder inherited either in autosomal recessive (AR) or autosomal dominant (AD) manner and characterized by blistering of the skin and mucous membranes. According to a subtype of EB, the oral manifestations and dental involvement vary in frequency and in severity. The most severe dental problems occur in patients with junctional epidermolysis bullosa (JEB) and severe generalized dystrophic epidermolysis bullosa (RDEB) and involve enamel erosion and development of blisters followed by painful oral wounds. Oral mucosa lesions decrease patients' quality of life and may contribute to difficulties in nutrition leading to cachexia. AIM: Assessment of efficacy of gentamicin 0.3% solution in the healing and preventing of oral erosions in patients with RDEB and evaluating its impact on the expression of type VII collagen. MATERIAL AND METHODS: The study included four female patients with RDEB, aged 16-42 who show different mutations in the COL7A1 gene and were administered the mouth rinse two times daily with a solution of 0.3% gentamycin for 4 consecutive weeks. Prior to and at the end of the study, the samples from oral mucosa were collected to estimate the expression of type VII collagen by immunofluorescence test. RESULTS: The clinical improvement of oral wounds healing and reduced number of new blisters and mucous membrane soreness as well as partial re-expression of type VII collagen was observed in all studied patients. CONCLUSIONS: Topical gentamicin therapy of oral cavity in RDEB patients resulted in clinical improvement of mucosal lesions and re-expression of collagen type VII.
ABSTRACT
INTRODUCTION: Mutations in the KRT1 gene encoding keratin 1 cause epidermolytic hyperkeratosis characterized by blistering in the neonatal period followed by ichthyotic hyperkeratosis in childhood and adolescent life. We observed a spectrum of clinical manifestations of blistering disorders caused by different mutations in the same KRT1 gene. AIM: To analyse the phenotypic spectrum of blistering disorders caused by the KRT1 mutations. MATERIAL AND METHODS: Four patients with an epidermal barrier defect manifesting as blistering with the KRT1 mutations were included to the study. The clinical course of the disease was analysed, histology, immunofluorescence and electron microscopic examinations were performed. RESULTS: An adult patient with severe ichthyosis with p.Asn188Lys mutation in exon 1 of KRT1 who occasionally develops blisters in adolescence represents epidermolytic hyperkeratosis, a newborn child who died 4 days after birth due to disruption of the epidermal barrier (extensive blister and erosions) with mutation p.Ser193Pro in the KTR1 gene and two adult sisters harbouring heterozygous mutation c.591+1A>G in the KRT1 gene who present superficial blisters induced by mild trauma from the birth up to adolescent life without ichthyosis suggesting the diagnosis of epidermolysis bullosa simplex. Histopathology in all adult patients showed cytoplasm disruption in keratinocytes of the stratum spinosum with keratohyalin granule-like structures and, on the ultrastructural level, the presence of keratin clumping confirming the pathology of keratin intermediate filaments. CONCLUSIONS: This study extends the knowledge of the clinical spectrum for the KRT1 gene mutations. This is the first description of familial dominant epidermolysis bullosa simplex linked to the KRT1 mutation.
ABSTRACT
INTRODUCTION: Cardiac abnormalities revealed in patients suffering from epidermolysis bullosa (EB) include dilated cardiomyopathy (DC) and aortopathy. DC is a rare but serious complication associated with an increased mortality, predominantly observed in recessive dystrophic EB. Echocardiography is the most available diagnostic tool used to detect heart disease in EB patients. AIM: To analyse echocardiographic results obtained in Polish EB patients and compare them between the EB group and healthy persons. MATERIAL AND METHODS: We analysed retrospectively echocardiograms of 23 patients with EB (14 F, mean age 17.3 years) performed from 2017 to 2019. The incidence of left ventricular (LV) systolic and diastolic dysfunction, right heart disease and congenital heart disease was evaluated. A comparison of echo-parameters between EB patients and 20 matched healthy subjects was performed. RESULTS: We did not find any cases of DC and aortopathy in the EB group. One bicuspid aortic valve case was revealed. Analysis of LV diastolic parameters showed that the mean value of mitral A velocity was significantly higher and the pulmonary venous flow D velocity was lower in the EB group than in controls. Tissue Doppler analysis revealed lower values of E' velocities of mitral annulus in the EB group, what may suggest discreetly slower LV relaxation, however, this will definitely require further research. CONCLUSIONS: Although most EB patients do not present cardiac symptoms, there is still a risk of developing cardiomyopathy associated with poor prognosis. It seems reasonable to perform a scheduled echocardiographic screening including LV systolic and diastolic function assessment to detect preclinical cardiac abnormalities.
ABSTRACT
Epidermolysis bullosa is a group of inherited blistering skin diseases resulting in most cases from missense mutations in KRT5 and KRT14 genes encoding the basal epidermal keratins 5 and 14. Here, we present a patient diagnosed with a localized subtype of epidermolysis bullosa simplex caused by a heterozygous mutation p.Ala428Asp in the KRT5 gene, that has not been previously identified. Moreover, a bioinformatic analysis of the novel mutation was performed, showing changes in the interaction network between the proteins. Identification of novel mutations and genotype-phenotype correlations allow to better understanding of underlying pathophysiologic bases and is important for genetic counselling, patients' management, and disease course prediction.
Subject(s)
Epidermolysis Bullosa Simplex/genetics , Keratin-5/genetics , Amino Acid Sequence , Amino Acid Substitution , Epidermolysis Bullosa Simplex/pathology , Female , Foot Dermatoses/genetics , Genetic Association Studies , Hand Dermatoses/genetics , Heterozygote , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Infant , Keratin-5/chemistry , Molecular Dynamics Simulation , Mutation, Missense , Protein Conformation , Protein Stability , Sequence Alignment , Tongue/pathologyABSTRACT
OBJECTIVES: It has previously been reported in a European case-control study with patients from Germany and France that CEL-HYB1, a hybrid allele of the carboxyl ester lipase (CEL) gene and its pseudogene CELP, increases susceptibility to chronic pancreatitis (CP). Here, we aimed to replicate this finding in Polish pediatric patients with CP. METHOD: The distribution of the CEL-HYB1 allele in a CP pediatric cohort (nâ¯=â¯147, median age at CP onset 7.6 years) with no history of alcohol/smoking abuse was compared with ethnically matched healthy controls (nâ¯=â¯500, median age 46 years). Screening was performed using long-range PCR followed by agarose gel-electrophoresis. RESULTS: We observed no significant difference in the carrier frequency of the CEL-HYB1 allele between CP patients (7/147, 4.8%) and controls (12/500, 2.4%; Pâ¯=â¯0.16). CONCLUSIONS: This study found no statistically significant association between CEL-HYB1 and chronic pancreatitis in a cohort of Polish pediatric CP patients.
Subject(s)
Lipase/genetics , Pancreatitis, Chronic/epidemiology , Pancreatitis, Chronic/genetics , Adolescent , Age of Onset , Alleles , Carrier State , Case-Control Studies , Child , Child, Preschool , Cohort Studies , Female , Gene Frequency , Humans , Infant , Male , Poland/epidemiology , Polymerase Chain ReactionABSTRACT
Genetically determined skin diseases, genodermatoses, are a group of rare disorders characterized by heterogeneous clinical course, prognosis and complex molecular pathology. In Epidermolysis Bullosa (EB) and Mendelian disorders of cornification (MeDOC) epidermal dysfunction occurs. Mutations in several dozen genes have been identified to be responsible for clinical symptoms of EB and MeDOC, which, in general, include: tendency to blister formation with skin fragility and abnormal keratinization, respectively. However, clinical symptoms of these diseases can be variable and genotype-phenotype correlations are only partially determined. Molecular diagnostics aimed at identification of mutations in affected individuals enables verification of clinical diagnosis, calculation of disease recurrence risk in other family members and, gradually, is also the basis for new therapies development. Nevertheless, even modern molecular technologies allow mutation detection in 80% of patients only. Hence, further, interdisciplinary scientific research are needed in order to increase detection rate and develop effective therapies.
Subject(s)
Epidermolysis Bullosa/diagnosis , Epidermolysis Bullosa/genetics , Mutation , Pathology, Molecular , Epidermis/pathology , Epidermis/physiopathology , Epidermolysis Bullosa/pathology , Epidermolysis Bullosa/physiopathology , HumansABSTRACT
OBJECTIVES: Genetic studies in adults/adolescent patients with chronic pancreatitis (CP) identified chymotrypsinogen C (CTRC) genetic variants but their association with CP risk has been difficult to replicate. To evaluate the risk of CP associated with CTRC variants in CP pediatric patients-control study. METHODS: The distribution of CTRC variants in CP pediatric cohort (nâ=â136, median age at CP onset 8 years) with no history of alcohol/smoking abuse was compared with controls (nâ=â401, median age 45). RESULTS: We showed that p.Arg254Trp (4.6%) and p.Lys247_Arg254del (5.3%) heterozygous mutations are frequent and significantly associated with CP risk in pediatric patients (odds ratio [OR]â=â19.1; 95% CI 2.8-160; Pâ=â0.001 and ORâ=â5.5; 95% CI 1.6-19.4; Pâ=â0.001, respectively). For the first time, we demonstrated that the c.180TT genotype of common p.Gly60Gly variant is strong, an independent CP risk factor (ORâ=â23; 95% CI 7.7-70; Pâ<â0.001) with effect size comparable to p.Arg254Trp mutation. The other novel observation is that common c.493+51C>A variant, both CA and AA genotype, is significantly underrepresented in CP compared with controls (15% vs 35%; ORâ=â0.33; 95% CI 0.19-0.59; Pâ<â0.001 and 2.8% vs 11%; ORâ=â0.24; 95% CI 0.06-0.85; Pâ=â0.027, respectively). CONCLUSIONS: Our study provides evidence that CTRC variants, including c.180TT (p.Gly60Gly) are strong CP risk factors. The c.493+51C>A variant may play a protective role against CP development.
Subject(s)
Chymotrypsinogen/genetics , Genetic Predisposition to Disease , Pancreatitis, Chronic/genetics , Serine Endopeptidases/genetics , Adult , Child , Female , Genetic Variation , Genotype , Humans , Male , Pancreatitis, Chronic/diagnosis , Risk Factors , Trypsin Inhibitor, Kazal Pancreatic/geneticsABSTRACT
BACKGROUND: Available data from adult patients do not reflect natural course of hereditary pancreatitis (HP) in children. To date, no study has assessed the clinical course of HP in children. OBJECTIVE: To investigate the clinical course of HP in children and compare it to non-HP group with chronic pancreatitis (CP). METHODS: A group of 265 children with CP, hospitalized from 1988 to 2014, were enrolled in the study. Medical records of those patients were reviewed for data on presentation, diagnostic findings and treatment. All children were screened for mutations in major pancreatitis-associated genes, i.e. PRSS1, SPINK1, and CFTR. RESULTS: HP was diagnosed in 41 children (15.5%). Family history was positive in 88% of children with HP. Mutations of PRSS1 gene were found in 80% (33/41) of HP patients. We detected p.R122H, p.R122C, p.N29I, and p.E79K mutation in 34% (14/41), 27% (11/41), 12% (5/41), and 7% (3/41) of HP patients, respectively. Patients with paternal inheritance had first symptoms earlier than those with maternal inheritance (5.9 vs. 9.1 years; P < 0.05). Children with HP showed more severe changes in ERCP then those from non-HP group (2.05 Cambridge grade, vs. 1.6°; P < 0.05). ESWL was performed more frequently in HP group (12.2% vs. 3.1%; P < 0.05). There was no difference in age of disease onset (7.98 vs. 8.9 years; NS), pancreatic duct stenting (46.3% vs. 33%; NS), or number of surgical interventions (12.2% vs. 14.3%; NS) between both groups. CONCLUSIONS: Children with HP reveal significantly more severe clinical presentation of the disease than non-HP patients, despite the same age of onset.
Subject(s)
Pancreatitis/genetics , Pancreatitis/pathology , Adolescent , Age of Onset , Body Mass Index , Carrier Proteins/genetics , Child , Child, Preschool , Cohort Studies , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Disease Progression , Exons , Female , Genetic Predisposition to Disease , Humans , Infant , Male , Mutation/genetics , Pancreatic Ducts/pathology , Pancreatitis, Chronic/genetics , Pancreatitis, Chronic/pathology , Polymorphism, Restriction Fragment Length , Retrospective Studies , Trypsin/genetics , Trypsin Inhibitor, Kazal Pancreatic , Young AdultABSTRACT
OBJECTIVES: The etiological factors of chronic pancreatitis (CP) in children differ from those in adults. To date, no study has assessed the clinical course of CP in young children. The aim of our study was to evaluate the etiology and the clinical presentation of the disease in children with disease onset before 5 years of age in comparison to later-onset of CP. METHODS: A total of 276 children with CP, hospitalized from 1988 to 2015, were enrolled in the study. Data on presentation, diagnostic findings, and treatment were reviewed. Two hundred sixty patients were screened for the most frequent mutations in major pancreatitis-associated genes, such as cationic trypsinogen/serine protease gene (PRSS1), serine protease inhibitor, Kazal type 1 gene (SPINK1), and cystic fibrosis transmembrane conductance regulator gene (CFTR). RESULTS: The disease onset before the age of 5 years occurred in 51 patients (group 1), the later onset in 225 patients (group 2). We found no significant discrepancies in distribution of the etiological factors between groups. The youngest patients (group 1) had more pancreatitis episodes (median 5.0 vs 3.00; Pâ<â0.05) and underwent surgeries more frequently (25.5% vs 8.9%; Pâ<â0.05). It could be associated with significantly longer follow-up in early onset group (median 6 vs 4 years; Pâ<â0.05). There were no differences in nutritional status or exocrine and endocrine pancreatic function. CONCLUSIONS: Early- and later-onset pancreatitis have similar etiological factors with predominance of gene mutations. The most frequent mutation found was p.Asn34Ser (N34S) in SPINK1 gene. The clinical presentation differed in number of pancreatitis episodes and frequency of surgeries.
Subject(s)
Age of Onset , Pancreatitis, Chronic/physiopathology , Adolescent , Child , Child, Preschool , Female , Genetic Predisposition to Disease , Humans , Infant , Longitudinal Studies , Male , Mutation , Pancreatitis, Chronic/etiology , Pancreatitis, Chronic/genetics , Risk FactorsABSTRACT
Ichthyosis is a rare, clinically heterogeneous group of 36 skin diseases with Mendelian inheritance, characterized by disorders of cornification (MeDOC, Mendelian Disorders Of Cornification). Currently there are 35 genes known which mutations are a molecular cause of different MeDOC. They encode proteins involved in the processes of keratinocytes differentiation, lipid synthesis and metabolism and DNA repair. Despite of this high molecular heterogeneity that leads to dysfunction and structure disorder of various epidermal components, the secondary effect of mutations in different genes is similar - disruption of the epidermal barrier and elevated transepidermal water loss. Disturbances in this basic epidermal protective function activate the repair mechanisms within the epidermis and lead i.a. to the primary symptom of MeDOC - hyperkeratosis. In this review we presented the current knowledge of biochemical processes and molecular causes of clinical symptoms based on selected examples of MeDOC.
Subject(s)
Epidermis/metabolism , Ichthyosis/metabolism , Cell Differentiation , DNA Repair , Epidermis/physiopathology , Humans , Ichthyosis/genetics , Ichthyosis/physiopathology , Keratinocytes/metabolism , Keratinocytes/physiology , Lipid Metabolism , MutationABSTRACT
Mutations of the human cationic trypsinogen gene (PRSS1) are frequently found in association with hereditary pancreatitis. The most frequent variants p.N29I and p.R122H are recognized as disease-causing mutations. Three pseudogene paralogs in the human trypsinogen family, including trypsinogen 6 (PRSS3P2), carry sequence variations in exon 3 that mimic the p.R122H mutation. In routine genetic testing of patients with chronic pancreatitis, we identified in two unrelated individuals similar gene conversion events of 24-71 nucleotides length between exon 3 of the PRSS1 (acceptor) and PRSS3P2 (donor) genes. The converted allele resulted in three nonsynonymous alterations c.343T>A (p.S115T), c.347G>C (p.R116P), and c.365_366delinsAT (p.R122H). Functional analysis of the conversion triple mutant revealed markedly increased autoactivation resulting in high and sustained trypsin activity in the presence of chymotrypsin C. This activation phenotype was identical to that of the p.R122H mutant. In addition, cellular secretion of the triple mutant from transfected HEK 293T cells was increased about twofold and this effect was attributable to mutation p.R116P. Our observations confirm and extend the notion that recombination events between members of the trypsinogen family can generate high-risk PRSS1 alleles. The pathogenic phenotype of the novel conversion is explained by a unique combination of increased trypsinogen activation and secretion.
Subject(s)
Gene Conversion , Pancreatitis, Chronic/genetics , Pseudogenes , Trypsin/genetics , Alleles , Cell Line , Child , Female , Humans , Male , Young AdultABSTRACT
Inherited metabolic disorders, also referred to as inborn errors of metabolism (IEM), are a group of congenital disorders caused by mutation in genomic or mitochondrial DNA. IEM are mostly rare disorders with incidence ranging from 1/50,000-1/150,000), however in total IEM may affect even 1/1000 people. A particular mutation affects specific protein or enzyme that improper function leads to alterations in specific metabolic pathway. Inborn errors of metabolism are monogenic disorders that can be inherited in autosomal recessive manner or, less frequently, in autosomal dominant or X-linked patterns. Some exceptions to Mendelian rules of inheritance have also been described. Vast majority of mutations responsible for IEM are small DNA changes affecting single or several nucleotides, although larger rearrangements were also identified. Therefore, the methods used for the identification of pathogenic mutations are mainly based on molecular techniques, preferably on Sanger sequencing. Moreover, the next generation sequencing technique seems to be another prospective method that can be successfully implemented for the diagnosis of inborn errors of metabolism. The identification of the genetic defect underlying the disease is not only indispensable for genetic counseling, but also might be necessary to apply appropriate treatment to the patient. Therapeutic strategies for IEM are continuously elaborated and tested (eg. enzyme replacement therapy, specific cells or organ transplantation or gene therapy, both in vivo and ex vivo) and have already been implemented for several disorders. In this article we present current knowledge about various aspects of IEM on the basis of our own experience and literature review.
Subject(s)
Genetic Testing/methods , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/therapy , Neonatal Screening/methods , Humans , Incidence , Infant, Newborn , Metabolism, Inborn Errors/epidemiology , Metabolism, Inborn Errors/genetics , Rare Diseases , Risk FactorsABSTRACT
Chronic pancreatitis (CP) is characterized by progressive damage to the exocrine and endocrine cell structures and pancreatic ducts with subsequent fibrosis of the organ. Patients with no apparent etiological factor are classified as having idiopathic CP (ICP). Genetic studies indicate the importance of mutations in the serine protease inhibitor, Kazal type 1 gene (SPINK1) in the pathogenesis of CP This report describes a case of a 29-year-old Polish-Vietnamese patient with the p.Asn34Ser (p.N34S) homozygous mutation in the SPINK1 gene. The patient was hospitalized due to pain of average intensity in the epigastric area which occurred for the first time in his life. Imaging examination showed the atrophy of the pancreatic parenchyma with the presence of numerous small calcifications and a single calcified lodgement with a diameter of 22 mm in the distal segment of Wirsung 's duct. Clinical interview did not reveal any obvious etiological pancreatitis risk factors implying the causative role of the p.Asn34Ser homozygous mutation of SPINK1 in this case as proven in our investigation.
Subject(s)
Carrier Proteins/genetics , Pancreatitis, Chronic/diagnosis , Pancreatitis, Chronic/genetics , Polymorphism, Genetic , Trypsin Inhibitor, Kazal Pancreatic/genetics , Adult , DNA Mutational Analysis , Female , Genetic Predisposition to Disease , Genotype , Humans , MutationABSTRACT
About 75% of cases of epidermolysis bullosa simplex result from mutations in KRT5 and KRT14 genes. Here, we report a family with a novel heterozygous missense mutation p.Leu418Gln in the KRT14 gene causing EBS of phenotype varying from EBS-loc to EBS-gen intermed. To the best of our knowledge, the family reported by us is the largest one in which two different phenotypes can be distinguished. The molecular dynamics simulations show that p.Leu418Gln mutation results in clear disruption of intermolecular π-stacking between KRT14:Tyr415 and KRT5:Tyr470, which in turn may affect putative phosphorylation site at KRT14:Thr414. This study further supports the importance of the EIATYR/KLLEGE motif in maintaining structural stability of KRT14:KRT5 heterodimer and indicates that physical properties of introduced amino acid can modulate the disease severity. The results obtained indicate further need of genotype-phenotype studies in EBS. In conclusion, genotype-based prognosis should be given to patients with caution.
Subject(s)
Epidermolysis Bullosa Simplex/genetics , Keratin-14/genetics , Amino Acid Substitution , Epidermolysis Bullosa Simplex/metabolism , Epidermolysis Bullosa Simplex/pathology , Female , Heterozygote , Humans , Keratin-14/chemistry , Keratin-5/chemistry , Male , Models, Molecular , Molecular Dynamics Simulation , Mutant Proteins/chemistry , Mutant Proteins/genetics , Mutation, Missense , Pedigree , Phenotype , Protein Interaction Domains and Motifs , Protein StabilitySubject(s)
Epidermolysis Bullosa Simplex/genetics , Gastric Outlet Obstruction/genetics , Genetic Predisposition to Disease , Muscular Dystrophies/genetics , Plectin/genetics , Pylorus/abnormalities , Urologic Diseases , Epidermolysis Bullosa Simplex/complications , Epidermolysis Bullosa Simplex/diagnosis , Follow-Up Studies , Gastric Outlet Obstruction/complications , Gastric Outlet Obstruction/diagnostic imaging , Humans , Infant, Newborn , Male , Monitoring, Physiologic , Muscular Dystrophies/complications , Muscular Dystrophies/diagnosis , Mutation , Pylorus/diagnostic imaging , Rare DiseasesABSTRACT
Cystic fibrosis is one of the most common recessively inherited monogenic disorders in the Caucasian population. The disease develops when pathogenic mutations of the CFTR gene, encoding a transmembrane conductance regulator, are present in both alleles. Cystic fibrosis is a multi-organ disease with heterozygous clinical course. High mortality of the disease is mainly due to progressive and irreversible changes in the lungs, leading to respiratory failure. Therefore, chronic obstructive pulmonary disease is the primary target in the search for effective therapeutic solutions. In recent years there has been a significant progress in the research on early diagnosis and treatment of cystic fibrosis. The newest strategies focus not only on the main symptoms of pulmonary disease (inflammation caused by bacterial infection and obstruction due to thickened mucus), but also on the correction of the cystic fibrosis cause - defective CFTR gene and its protein product. Therapeutics like VX-770 and PTC124, intended for patients with a specific genotype, have already emerged on the U.S. and European medical market. They modulate the defective CFTR protein function or act on the level of abnormal CFTR mRNA, respectively. At the same time scientists develop new solutions in the field of somatic gene therapy in order to increase the efficiency of corrected CFTR delivery to the respiratory tract cells and to maintain its expression in the target cells. In this review we discuss the progress achieved in the development of therapy that is at the stage of both preclinical and clinical phases.