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1.
Clin Genet ; 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38774940

RESUMO

Skeletal dysplasias are a heterogeneous group of disorders presenting mild to lethal defects. Several factors, such as genetic, prenatal, and postnatal environmental may contribute to reduced growth. Fourteen families of Pakistani origin, presenting the syndromic form of short stature either in the autosomal recessive or autosomal dominant manner were clinically and genetically investigated to uncover the underlying genetic etiology. Homozygosity mapping, whole exome sequencing, and Sanger sequencing were used to search for the disease-causing gene variants. In total, we have identified 13 sequence variants in 10 different genes. The variants in the HSPG2 and XRCC4 genes were not reported previously in the Pakistani population. This study will expand the mutation spectrum of the identified genes and will help in improved diagnosis of the syndromic form of short stature in the local population.

2.
Microsc Res Tech ; 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38747100

RESUMO

The bio-reductive fabrication of nanomaterials is a developing arena of study that seeks to fabricate nanoparticles (NPs) using microorganisms, plants, and animal blood. However, the chemical approach of AgNPs fulfills the need of abundant need of NPs. In contrast, chemically fabricated AgNPs are more toxic than biological AgNPs. Therefore, the current study aimed to assess and evaluate the chemically fabricated silver nanoparticles (AgNPs) for their possible toxicity in Common carp fish (Cyprinus carpio). The chemically synthesized silver nanoparticles were purchased from the market and applied for their possible toxicity. The chemically fabricated AgNPs were used against the Cyprinus carpio for bioaccumulation in different organs and histological alterations in the intestine and muscles. The results revealed that the AgNPs were mostly accumulated in the intestines followed by the gills, liver, and muscles (p < .05). The accumulated AgNPs caused histological alterations in gills and intestines at the highest concentration (0.08 mg/L). However, no alterations were observed by the middle and lowest concentration of AgNPs, particularly, in the intestine. In conclusion, more extensive research is required to establish the hazards related to the use of nanoparticles to disclose their negative effects on fish and the aquatic environment. REASEARCH HIGHLIGHTS: The chemical method fabricates a large amount of AgNPs Additionally, considered more toxic than the bio-reductive method AgNPs have excellent and diverse applications AgNPs deposited in various organs and cause histological changes.

3.
J Pak Med Assoc ; 74(4): 701-705, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38751265

RESUMO

Objective: To evaluate patient satisfaction and its associated factors in teaching hospitals. METHODS: The cross-sectional, analytical study was conducted from September to December 2022 at three publicsector medical teaching hospitals in Peshawar, Pakistan, and comprised adult patients of either admitted to various hospital wards for at least 2 days. Data was collected using a predesigned a closed-ended questionnaire assessing patient satisfaction in different domains like, facilitation at the admission, professional knowledge and skills of the attending doctors, quality of diagnostic and nursing services, and basic amenities. Data was analysed using SPSS version origin Pro 2022a. RESULTS: There were 473 patients with a male-female ratio of 3:1, with mean age 43.3+14.7 years (range: 11-85 years), and mean hospital stay 5.96+3.37 days (range: 2-18 days). Of the 2,365 response statements for facilitation at the admission counter, 2,051(87%) were positive; of the 2,365 statements for attending doctors, 2,012(85%) were positive; of the 2,838 statements for nursing care, 2,122(75%) were positive; of 946 statements for diagnostic services, 627(66%) were positive; and of the 3,311 statements for basic amenities at the hospital, 1,246(38%) were positive. Overall, of the 11,825 response statements, 8058(68%) were positive. The patient satisfaction was significantly co-related with education and hospital stay (p<0.05). Conclusion: Patients were found to be generally satisfied with healthcare services, but not with the provision of basic amenities.


Assuntos
Hospitais de Ensino , Satisfação do Paciente , Humanos , Paquistão , Masculino , Feminino , Adulto , Estudos Transversais , Pessoa de Meia-Idade , Adolescente , Idoso , Adulto Jovem , Satisfação do Paciente/estatística & dados numéricos , Criança , Idoso de 80 Anos ou mais , Inquéritos e Questionários , Competência Clínica , Corpo Clínico Hospitalar/psicologia
4.
Clin Genet ; 104(4): 499-501, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37311648

RESUMO

A short report with two affected siblings from consanguineous family born with intellectual disability, motor disability, language deficit, and hearing impairment and found to carry biallelic nonsense variant in KPTN gene known to be associated with KPTN gene related syndrome.


Assuntos
Pessoas com Deficiência , Perda Auditiva , Deficiência Intelectual , Transtornos Motores , Humanos , Consanguinidade , Perda Auditiva/genética , Deficiência Intelectual/genética , Proteínas dos Microfilamentos/genética , Linhagem , Fenótipo , Síndrome
5.
JAMA Dermatol ; 159(7): 745-749, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-37195706

RESUMO

Importance: Grover disease (GD), a truncal eruption that typically occurs in older individuals, is exacerbated by sweating, irradiation, cancers, medications, kidney failure, and organ transplantation. The pathobiology of GD remains unknown. Objective: To determine if damaging somatic single-nucleotide variants (SNVs) are associated with GD. Design, Setting, and Participants: In this retrospective case series, we identified consecutive patients from a dermatopathology archive over a 4-year period (January 2007 to December 2011) who had 1 biopsy with a clinical diagnosis of GD confirmed via histopathologic findings and another non-GD biopsy. Participant DNA was extracted from both biopsy tissues and sequenced to high depth with a 51-gene panel to screen for SNVs in genes previously associated with acantholysis and Mendelian disorders of cornification. Analysis took place between 2021 and 2023. Main Outcomes and Measures: Comparative analysis of sequencing data from paired GD and control tissue was employed to identify SNVs predicted to affect gene function, which were exclusive to, or highly enriched in, GD tissue. Results: Overall, 12 of 15 cases of GD (12 men and 3 women; mean [SD] age, 68.3 [10.0] years) were associated with C>T or G>A ATP2A2 SNVs in GD tissue; all were predicted to be highly damaging via combined annotation dependent depletion (CADD) scores, and 4 were previously associated with Darier disease. In 9 cases (75%), the GD-associated ATP2A2 SNV was absent from control tissue DNA, and in 3 cases (25%), ATP2A2 SNVs were enriched 4- to 22-fold in GD vs control tissue. Conclusions and Relevance: In this case series study of 15 patients, damaging somatic ATP2A2 SNVs were associated with GD. This discovery expands the spectrum of acantholytic disorders associated with ATP2A2 SNVs and highlights the role of somatic variation in acquired disorders.


Assuntos
Acantólise , Ictiose , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático , Idoso , Feminino , Humanos , Masculino , Acantólise/genética , Acantólise/patologia , Doença de Darier/genética , Ictiose/diagnóstico , Ictiose/genética , Estudos Retrospectivos
6.
BMC Ophthalmol ; 23(1): 116, 2023 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-36959549

RESUMO

BACKGROUND: Retinitis pigmentosa (RP) is one of the most frequent hereditary retinal diseases that often starts with night blindness and eventually leads to legal blindness. Our study aimed to identify the underlying genetic cause of autosomal recessive retinitis pigmentosa (arRP) in a consanguineous Pakistani family. METHODS: Following a detailed ophthalmological examination of the patients by an ophthalmologist, whole-exome sequencing was performed on the proband's DNA to delineate the genetic cause of RP in the family. In-depth computational methods, in-silico analysis, and familial co-segregation study were performed for variant detection and validation. RESULTS: We studied an inbred Pakistani family with two siblings affected by retinitis pigmentosa. The proband, a 32 years old female, was clinically diagnosed with RP at the age of 6 years. A classical night blindness symptom was reported in the proband since her early childhood. OCT report showed a major reduction in the outer nuclear layer and the ellipsoid zone width, leading to the progression of the disease. Exome sequencing revealed a novel homozygous missense mutation (c.938C > T;p.Thr313Ile) in exon 12 of the PDE6B gene. The mutation p.Thr313Ile co-segregated with RP phenotype in the family. The altered residue (p.Thr313) was super conserved evolutionarily across different vertebrate species, and all available in silico tools classified the mutation as highly pathogenic. CONCLUSION: We present a novel homozygous pathogenic mutation in the PDE6B gene as the underlying cause of arRP in a consanguineous Pakistani family. Our findings highlight the importance of missense mutations in the PDE6B gene and expand the known mutational repertoire of PDE6B-related RP.


Assuntos
Cegueira Noturna , Retinose Pigmentar , Pré-Escolar , Feminino , Humanos , Consanguinidade , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética , Análise Mutacional de DNA , Proteínas do Olho/genética , Mutação , Cegueira Noturna/genética , Paquistão , Linhagem , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/genética , Homozigoto
7.
Genes (Basel) ; 14(2)2023 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-36833358

RESUMO

BACKGROUND: Inherited isolated nail clubbing is a very rare Mendelian condition in humans, characterized by enlargement of the terminal segments of fingers and toes with thickened nails. Mutations in two genes have been reported to cause isolated nail clubbing in humans, which are the SLCO2A1 gene and the HPGD gene. OBJECTIVES: An extended Pakistani family having two affected siblings born of unaffected consanguineous union was included in the study. Predominant isolated congenital nail clubbing (ICNC) without any other systemic abnormalities was observed, which we aimed to characterize at clinico-genetic level. METHODS: Whole exome coupled with Sanger sequencing were employed to uncover the sequence variant as a cause of the disease. Furthermore, protein modeling was carried out to reveal the predicted possible effect of the mutation at the protein level. RESULTS: Whole exome sequencing data analysis revealed a novel biallelic sequence variant (c.155T>A; p.Phe52Tyr) in the SLCO2A1 gene. Further, Sanger sequencing analysis validated and confirmed the segregation of the novel variant in the entire family. Subsequently, protein modeling of the wild-type and mutated SLCO2A1 revealed broad-scale change, which might compromise the proteins' secondary structure and function. CONCLUSION: The present study adds another mutation to the SLCO2A1-related pathophysiology. The involvement of SLCO2A1 in the pathogenesis of ICNC may open exciting perceptions of this gene in nail development/morphogenesis.


Assuntos
Unhas Malformadas , Transportadores de Ânions Orgânicos , Osteoartropatia Hipertrófica Primária , Humanos , Dinoprostona/metabolismo , Osteoartropatia Hipertrófica Primária/genética , Mutação de Sentido Incorreto , Mutação , Transportadores de Ânions Orgânicos/genética
8.
Int J Dermatol ; 62(5): 672-680, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36789964

RESUMO

BACKGROUND: Congenital ichthyosis is a diverse group of keratinization disorders associated with generalized scaling of skin of varying severity. The non-syndromic forms of congenital ichthyosis are further grouped into common ichthyosis (ichthyosis vulgaris and X-linked ichthyosis), autosomal recessive congenital ichthyosis, and keratopathic ichthyosis. OBJECTIVE: To identify sequence variants involved in different forms of hereditary ichthyoses. METHODS: We studied eight families with different types of ichthyosis including four families with autosomal recessive congenital ichthyosis and four families with common ichthyosis. Whole exome sequencing and PCR based genotyping was carried out to find out the molecular basis of disease. RESULTS: In one family, a novel duplication sequence variant NM_002016.2:c.2767dupT; NP_002007.1:p.Ser923PhefsTer2 was identified in FLG gene; in four families a previously reported nonsense sequence variant NM_000359.3:c.232C>T; NP_002007.1:p.Arg78Ter was identified in TGM1 gene, while, in three families of X-linked recessive ichthyosis, the whole STS gene (NM_001320752.2; NP_001307681.2) regions were deleted. STUDY LIMITATION: Gene expression studies have not been performed that would have strengthened the findings of computational analysis. CONCLUSION: This study highlights the significance of the c.232C>T variant in the TGM1 gene as a possible founder mutation, complete STS gene deletion as reported previously in Pakistani population, while novel sequence variant in the FLG gene expands the spectrum of variations in this gene. These findings may be used for genetic counseling of the studied families.


Assuntos
Eritrodermia Ictiosiforme Congênita , Ictiose Lamelar , Ictiose , Humanos , Eritrodermia Ictiosiforme Congênita/genética , Ictiose/genética , Ictiose Lamelar/genética , Mutação , Paquistão
9.
Hum Mol Genet ; 32(7): 1184-1192, 2023 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-36355422

RESUMO

Congenital hearing impairment (HI) is a genetically highly heterogeneous disorder in which prompt recognition and intervention are crucial to optimize outcomes. In this study, we used exome sequencing to investigate a large consanguineous Pakistani family with eight affected individuals showing bilateral severe-to-profound HI. This identified a homozygous splice region variant in STX4 (c.232 + 6T>C), which causes exon skipping and a frameshift, that segregated with HI (two-point logarithm of odds (LOD) score = 5.9). STX4, a member of the syntaxin family, is a component of the SNARE machinery involved in several vesicle transport and recycling pathways. In silico analysis showed that murine orthologue Stx4a is highly and widespread expressed in the developing and adult inner ear. Immunofluorescent imaging revealed localization of STX4A in the cell body, cell membrane and stereocilia of inner and outer hair cells. Furthermore, a morpholino-based knockdown of stx4 in zebrafish showed an abnormal startle response, morphological and developmental defects, and a disrupted mechanotransduction function in neuromast hair cells measured via FM1-43 uptake. Our findings indicate that STX4 dysfunction leads to HI in humans and zebrafish and supports the evolutionary conserved role of STX4 in inner ear development and hair cell functioning.


Assuntos
Mecanotransdução Celular , Peixe-Zebra , Adulto , Humanos , Animais , Camundongos , Peixe-Zebra/genética , Proteínas Qa-SNARE/genética , Audição/genética , Células Ciliadas Auditivas Externas
10.
Front Pharmacol ; 14: 1328308, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38269277

RESUMO

Amid the ongoing monkeypox outbreak, there is an urgent need for the rapid development of effective therapeutic interventions capable of countering the immune evasion mechanisms employed by the monkeypox virus (MPXV). The evasion strategy involves the binding of the F3L protein to dsRNA, resulting in diminished interferon (IFN) production. Consequently, our current research focuses on utilizing virtual drug screening techniques to target the RNA binding domain of the F3L protein. Out of the 954 compounds within the South African natural compound database, only four demonstrated notable docking scores: -6.55, -6.47, -6.37, and -6.35 kcal/mol. The dissociation constant (KD) analysis revealed a stronger binding affinity of the top hits 1-4 (-5.34, -5.32, -5.29, and -5.36 kcal/mol) with the F3L in the MPXV. All-atom simulations of the top-ranked hits 1 to 4 consistently exhibited stable dynamics, suggesting their potential to interact effectively with interface residues. This was further substantiated through analyses of parameters such as radius of gyration (Rg), Root Mean Square Fluctuation, and hydrogen bonding. Cumulative assessments of binding free energy confirmed the top-performing candidates among all the compounds, with values of -35.90, -52.74, -28.17, and -32.11 kcal/mol for top hits 1-4, respectively. These results indicate that compounds top hit 1-4 could hold significant promise for advancing innovative drug therapies, suggesting their suitability for both in vivo and in vitro experiments.

11.
J Med Case Rep ; 16(1): 66, 2022 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-35168679

RESUMO

BACKGROUND: Pyruvate kinase deficiency is an exceptionally rare autosomal recessive Mendelian disorder caused by bi-allelic pathogenic variants in the PKLR gene. It is mainly characterized by chronic nonspherocytic hemolytic anemia though other symptoms such as splenomegaly, hepatomegaly, pallor, fatigue, iron overload, shortness of breath, hyperbilirubinemia, and gallstones might also prevail. CASE PRESENTATION: We present here a novel genetic defect in the PKLR gene that correlates with pyruvate kinase deficiency phenotype in a consanguineous family from North-Western Pakistan. The family included three affected individuals who were all born to consanguineous parents. The proband, a 13-year-old female of Pashtun ethnicity, showed chronic nonautoimmune hemolytic anemia since birth, extremely low hemoglobin (7.6 g/dL) and pyruvate kinase (12.4 U/g Hb) levels, splenomegaly, and hepatomegaly. Bone marrow aspirate showed a markedly decreased myeloid to erythroid ratio and hypercellular marrow particles due to hyperplasia of the erythroid elements. Molecular characterization of the proband's genomic DNA uncovered a likely pathogenic homozygous missense variant p.[D339N] in exon 7 of the PKLR gene. In-depth in silico analysis and familial cosegregation implies p.[D339N] as the likely cause of pyruvate kinase deficiency in this family. Further in vitro or in vivo studies are required to validate the impact of p.[D339N] on protein structure and/or stability, and to determine its role in the disease pathophysiology. CONCLUSIONS: In summary, these findings suggest a novel genetic defect in the PKLR gene as a likely cause of pyruvate kinase deficiency, thus further expanding the mutational landscape of this rare Mendelian disorder.


Assuntos
Anemia Hemolítica Congênita não Esferocítica , Erros Inatos do Metabolismo dos Piruvatos , Adolescente , Anemia Hemolítica Congênita não Esferocítica/genética , Feminino , Humanos , Mutação , Paquistão , Piruvato Quinase/deficiência , Piruvato Quinase/genética , Erros Inatos do Metabolismo dos Piruvatos/genética
12.
J Clin Lab Anal ; 36(1): e24127, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34877714

RESUMO

BACKGROUND: Woodhouse-Sakati syndrome is a rare autosomal recessive disease with endocrine and neuroectodermal aberrations with heterogeneous phenotypes and disease course. The most common phenotypes of the disease are progressive sensorineural hearing loss and alopecia, mild-to-moderate mental retardation and hypogonadism. The disease results from mutations in the DCAF17 gene. METHOD: Here, we reported a large consanguineous pedigree with multiple affected individuals with Woodhouse-Sakati syndrome phenotypes. Laboratory tests confirmed the endocrine perturbance in affected individuals. To find out the underlying genetic change, whole-exome sequencing was carried out. RESULT: Analysis of the exome data identified a splicing-site deletion NM_025000.3:c.1423-1_1425delGACA in DCAF17 gene. Sanger sequencing confirmed the co-segregation of the variant with the disease phenotypes in the family. CONCLUSION: The variant is predicted to cause aberrant splicing, i.e., exon skipping, resulting in the translation of a truncated functionless protein which results in appearance of typical phenotypic features and clinical laboratory findings of Woodhouse-Sakati syndrome in affected members of the family.


Assuntos
Alopecia/genética , Arritmias Cardíacas/genética , Doenças dos Gânglios da Base/genética , Diabetes Mellitus/genética , Hipogonadismo/genética , Deficiência Intelectual/genética , Mutação/genética , Proteínas Nucleares/genética , Complexos Ubiquitina-Proteína Ligase/genética , Adolescente , Alopecia/patologia , Alopecia/fisiopatologia , Arritmias Cardíacas/patologia , Arritmias Cardíacas/fisiopatologia , Doenças dos Gânglios da Base/patologia , Doenças dos Gânglios da Base/fisiopatologia , Criança , Consanguinidade , Análise Mutacional de DNA , Diabetes Mellitus/patologia , Diabetes Mellitus/fisiopatologia , Fácies , Feminino , Humanos , Hipogonadismo/patologia , Hipogonadismo/fisiopatologia , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Masculino , Linhagem , Isoformas de Proteínas/genética , Couro Cabeludo/patologia
13.
Angew Chem Int Ed Engl ; 61(4): e202114951, 2022 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-34816561

RESUMO

The development of highly active and stable bifunctional noble-metal-based electrocatalysts for the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER) is a crucial goal for clean and renewable energy, which still remains challenging. Herein, we report an efficient and stable catalyst comprising a Co single atom incorporated in an RuO2 sphere for HER and OER, in which the Co single atom in the RuO2 sphere was confirmed by XAS, AC-STEM, and DFT. This tailoring strategy uses a Co single atom to modify the electronic structures of the surrounding Ru atoms and thereby remarkably elevates the electrocatalytic activities. The catalyst requires ultralow overpotentials, 45 mV for HER and 200 mV for OER, to deliver a current density of 10 mA cm-2 . The theoretical calculations reveal that the energy barriers for HER and OER are lowered after incorporation of a cobalt single atom.

16.
Microsc Res Tech ; 84(10): 2302-2310, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34048107

RESUMO

Over the years, nanoscience and the application of nanomaterials have gained the attention of researchers due to their enormous application history. Especially, the application of AgNPs providing innovative solutions to a wide range of environmental issues, for instance, wastewater treatment, bioremediations, and environmental sensing. Besides all these, the environmental application of silver nanomaterials causes severe problems in the terrestrial and aquatic ecosystems. For their concern, the present study was conducted to expose rainbow trout fish (Oncorhynchus mykiss) to different concentrations of silver nanoparticles for 25 days. In the current study, mortality (LC50 ), accumulation, and histopathological changes were analyzed. The results have revealed that the silver nanoparticles were mostly accumulated in the liver followed by the intestine, gill, and muscles. The microscopic analysis has shown that the accumulation of silver nanoparticles led to histological changes in gill and intestinal tissues. Necrosis, degeneration, mucus substance on the surface of gill lamella, cell lysis, and gill lamella atrophy were found at (0.04 mg/L) and (0.06 mg/L). The findings in the current study showed less toxicity in the sense of mortality and accumulation of AgNPs. Therefore, further systematic studies are needed to access the influence of silver nanoparticles on the aquatic ecosystem.


Assuntos
Nanopartículas Metálicas , Oncorhynchus mykiss , Poluentes Químicos da Água , Animais , Ecossistema , Brânquias , Nanopartículas Metálicas/toxicidade , Prata/toxicidade , Poluentes Químicos da Água/análise
17.
3 Biotech ; 10(10): 452, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33062580

RESUMO

In the current study, aerial parts (leaves, stem and shoots) of C. album were extracted with methanol and subjected to phytochemical and HPLC analysis. Agar well diffusion method was used for anti-bacterial activity against Gram-negative strains Escherichia coli, Salmonella typhi, Klebsiella, Pseudomonas aeruginosa and Gram-positive Bacillus cereus, Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus. Burn was induced through flame heated metal rod on mice. C. album ointment (2% w/w), Vaseline (vehicle) and silver sulfadiazine (standard) were topically applied thrice daily for 15 days. Wound area was measured on day 0, 5, 10 and 15. On last day, the wound tissues were excised and subjected to histopathological, quantitative PCR and immunohistochemical analysis. Phenols, alkaloids, phytosterols, tannins, saponins, flavonoids, carbohydrates and glycosides were detected in phytochemical analysis. HPLC chromatogram displayed peaks for rutin, quercetin, ascorbic acid, gallic acid and various other phyto-constituents. The extract exhibited zone of inhibition in millimeter (mm) against E. coli (12.3 ± 0.57), S. typhyi (14.6 ± 1.52), Klebsiella (11.8 ± 0.76), P. aeruginosa (12.3 ± 0.57), B. cereus (12.5 ± 1.29), S. aureus (18.3 ± 2.08), and MRSA (11.8 ± 0.76). The wound area in C. album group was significantly (60%) reduced as compared to vehicle group (11%). Histological analysis showed complete re-epithelialization and fine tissue in extract treated group. qPCR data revealed up-regulation of EGF, PDGF and TGF-ß1 genes in extract treated group. Similarly, immunohistochemistry results confirmed heightened EGFR expression in extract treated group. Our findings suggest that C. album can promote wound healing and tissue regeneration through control of burns related infection and modulation of growth factors and its receptors.

18.
Curr Mol Med ; 19(10): 705-718, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456517

RESUMO

Age-related macular degeneration (AMD) is an eye disorder affecting predominantly the older people above the age of 50 years in which the macular region of the retina deteriorates, resulting in the loss of central vision. The key factors associated with the pathogenesis of AMD are age, smoking, dietary, and genetic risk factors. There are few associated and plausible genes involved in AMD pathogenesis. Common genetic variants (with a minor allele frequency of >5% in the population) near the complement genes explain 40-60% of the heritability of AMD. The complement system is a group of proteins that work together to destroy foreign invaders, trigger inflammation, and remove debris from cells and tissues. Genetic changes in and around several complement system genes, including the CFH, contribute to the formation of drusen and progression of AMD. Similarly, Matrix metalloproteinases (MMPs) that are normally involved in tissue remodeling also play a critical role in the pathogenesis of AMD. MMPs are involved in the degradation of cell debris and lipid deposits beneath retina but with age their functions get affected and result in the drusen formation, succeeding to macular degeneration. In this review, AMD pathology, existing knowledge about the normal and pathological role of complement system proteins and MMPs in the eye is reviewed. The scattered data of complement system proteins, MMPs, drusenogenesis, and lipofusogenesis have been gathered and discussed in detail. This might add new dimensions to the understanding of molecular mechanisms of AMD pathophysiology and might help in finding new therapeutic options for AMD.


Assuntos
Proteínas do Sistema Complemento/metabolismo , Degeneração Macular/patologia , Metaloproteinases da Matriz/metabolismo , Animais , Humanos , Degeneração Macular/enzimologia , Degeneração Macular/imunologia
19.
Ann Hum Genet ; 83(6): 477-482, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31173343

RESUMO

Ciliopathies are a clinically and genetically heterogeneous group of disorders often exhibiting phenotypic overlap and caused by abnormalities in the structure or function of cellular cilia. As such, a precise molecular diagnosis is important for guiding clinical management and genetic counseling. In the present study, two Pakistani families comprising individuals with overlapping clinical features suggestive of a ciliopathy syndrome, including intellectual disability, obesity, congenital retinal dystrophy, and hypogonadism (in males), were investigated clinically and genetically. Whole-exome sequencing identified the likely causes of disease as a novel homozygous frameshift mutation (NM_152384.2: c.196delA; p.(Arg66Glufs*12); family 1) in BBS5, and a nonsense mutation (NM_019892.5:c.1879C>T; p.Gln627*; family 2) in INPP5E, previously reported in an extended Pakistani family with MORM syndrome. Our findings expand the molecular spectrum associated with BBS5 mutations in Pakistan and provide further supportive evidence that the INPP5E mutation is a common cause of ciliopathy in Northern Pakistan, likely representing a regional founder mutation. This study also highlights the value of genomic studies in Pakistan for families affected by rare heterogeneous developmental disorders and where clinical phenotyping may be limited by geographical and financial constraints. The identification of the spectrum and frequency of disease-causing variants within this setting enables the development of population-specific genetic testing strategies targeting variants common to the local population and improving health care outcomes.


Assuntos
Ciliopatias/diagnóstico , Ciliopatias/genética , Proteínas do Citoesqueleto/genética , Mutação , Proteínas de Ligação a Fosfato/genética , Monoéster Fosfórico Hidrolases/genética , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Efeito Fundador , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Paquistão , Linhagem , Adulto Jovem
20.
Int J Dermatol ; 58(8): 946-952, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31077348

RESUMO

BACKGROUND: Autosomal recessive wooly hair/hypotrichosis is an inherited disorder of hair characterized by less dense, short, and tightly curled hair on the scalp and sometimes less dense to complete absence of eyebrows and eyelashes. Autosomal recessive wooly hair/hypotrichosis phenotypes are mostly associated with pathogenic sequence variants in LIPH and LPAR6 genes. METHODS: To find out the molecular basis of the disease, five families with autosomal recessive wooly hair/hypotrichosis were recruited for genetic analysis. Direct Sanger sequencing of LIPH and LPAR6 genes was carried out using BigDye chain termination chemistry. P2RY5 protein homology models were developed to study the effect of mutation on protein structure in a family having novel mutation. RESULTS: Sanger sequencing revealed a novel homozygous missense mutation (c.47A>T) in the LPAR6 gene in family A, while recurrent mutation (c.436G>A) was detected in the rest of the four families (B-E). Protein homology models for both native and mutant P2RY5 protein were developed to study the difference in subtle structural features because of Lys16Met (K16M) mutation. We observed that P2RY5K16M mutation results decrease in the number of ionic interactions detrimental to the protein stability. Protein modeling studies revealed that the novel mutation identified here decreased the number of ionic interactions by affecting physicochemical parameters of the protein, leading to an overall decrease in protein stability with no major secondary structural changes. CONCLUSION: The molecular analysis further confirms the frequent involvement of LPAR6 in autosomal recessive wooly hair/hypotrichosis, while the bioinformatic study revealed that the missense mutation destabilizes the overall structure of P2RY5 protein.


Assuntos
Genes Recessivos/genética , Doenças do Cabelo/genética , Cabelo/anormalidades , Hipotricose/genética , Receptores de Ácidos Lisofosfatídicos/genética , Biologia Computacional , Consanguinidade , Feminino , Humanos , Masculino , Mutação de Sentido Incorreto , Paquistão , Linhagem , Fenótipo , Estrutura Secundária de Proteína/genética , Receptores de Ácidos Lisofosfatídicos/química , Receptores Purinérgicos P2/química , Receptores Purinérgicos P2/genética , Homologia de Sequência de Aminoácidos
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