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1.
Indian J Med Res ; 142(4): 414-25, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26609033

RESUMO

BACKGROUND & OBJECTIVES: Mucopolysaccharidosis type VI (MPS VI) is a rare, autosomal recessive lysosomal storage disorder caused by deficient enzymatic activity of N-acetyl galactosamine-4-sulphatase resulting from mutations in the arylsulphatase B (ARSB) gene. The ARSB gene is located on chromosome 5q11-q13 and is composed of eight exons. More than hundred ARSB mutations have been reported so far, but the mutation spectrum of MPS VI in India is still unknown. Hence, the aim of the present study was to identify the mutational spectrum in patients with MPS VI in India and to study the genotype-phenotype association and functional outcomes of these mutations. METHODS: Molecular characterization of the ARSB gene by Sanger sequencing was done for 15 patients (aged 15 months to 11 yr) who were enzymatically confirmed to have MPS VI. Age of onset, clinical progression and enzyme activity levels in each patient were studied to look for genotype-phenotype association. Haplotype analysis performed for unrelated patients with the recurring mutation W450C, was suggestive of a founder effect. Sequence and structural analyses of the ARSB protein using standard software were carried out to determine the impact of detected mutations on the function of the ARSB protein. RESULTS: A total of 12 mutations were identified, of which nine were novel mutations namely, p.D53N, p.L98R, p.Y103SfsX9, p.W353X, p.H393R, p.F166fsX18, p.I220fsX5, p.W450L, and p.W450C, and three were known mutations (p.D54N, p.A237D and p.S320R). The nine novel sequence variants were confirmed not to be polymorphic variants by performing sequencing in 50 unaffected individuals from the same ethnic population. INTERPRETATION & CONCLUSIONS: Nine novel mutations were identified in MPS VI cases from India in the present study. The study also provides some insights into the genotype-phenotype association in MPS VI.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Mucopolissacaridose VI/genética , N-Acetilgalactosamina-4-Sulfatase/genética , Criança , Pré-Escolar , Éxons/genética , Feminino , Haplótipos , Humanos , Índia , Lactente , Masculino , Mucopolissacaridose VI/patologia , Mutação
2.
Am J Med Genet A ; 164A(6): 1443-53, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24677745

RESUMO

Mucopolysaccharidosis (MPS) type VI or Maroteaux-Lamy syndrome is a very rare autosomal recessive lysosomal storage disease, caused by a deficiency of the enzyme N-acetylgalactosamine-4-sulfatase (Arylsulfatase B, ARSB). Clinical examination, biochemical studies, and molecular genetic analyses have been performed in 17 patients affected with MPS VI from 15 unrelated families from Thailand, India, and Turkey. Large ear lobule appears to be a newly recognized finding of this syndrome. Mutation analysis of the ARSB gene revealed seven missense and three frameshift mutations of which eight were novel. Novel missense mutations were p.Asp53Asn, p.Val376Glu, p.Glu390Lys, p.Pro445Leu, and p.Trp450Cys, while an Indian patient was homozygous for two novel missense mutations (p.Pro445Leu and p.Trp450Cys). Three novel frameshift mutations were p.Pro70fsX123, p.Ser403fs, and p.Thr526fs. Two previously reported mutations, p.Arg160Gln and p.Leu321Pro, were also observed in our cohort. The amino acid Arg160 appears to be the mutational hot spot for the ARSB gene. Five patients homozygous for p.Leu321Pro mutation had early onset of the disease, and haplotype analysis showed that the mutation is a founder mutation in Turkish population.


Assuntos
Anormalidades Múltiplas/genética , Mucopolissacaridose VI/epidemiologia , Mucopolissacaridose VI/genética , N-Acetilgalactosamina-4-Sulfatase/genética , Adolescente , Adulto , Sequência de Bases , Criança , Mapeamento Cromossômico , Análise Mutacional de DNA , Feminino , Mutação da Fase de Leitura , Haplótipos/genética , Humanos , Índia/epidemiologia , Iraque/epidemiologia , Masculino , Repetições de Microssatélites/genética , Mucopolissacaridose VI/patologia , Mutação de Sentido Incorreto , Dobramento de Proteína , Deficiências na Proteostase/genética , Turquia/epidemiologia , Adulto Jovem
3.
J Inherit Metab Dis ; 37(2): 263-8, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23974652

RESUMO

OBJECTIVE: To assess oral manifestations of 17 patients with mucopolysaccharidosis type VI (MPS VI) or Maroteaux-Lamy syndrome. METHODS: We performed comprehensive oral examinations in 17 patients with MPS VI. Panoramic radiographs was performed only in 14 patients. All patients were of Thai, Turkish, and Indian origins. Ten of 17 patients had enzyme replacement therapy (ERT) (Naglazyme). Most Turkish patients (10/11) were on ERT. The Thai and Indian patients have never had ERT. RESULTS: Oral and radiographic examinations showed that hypoplastic mandibular condyles (93.3 %), malposition of unerupted teeth (92.9 %), large dental follicles (92.3 %), anterior open bite (86.7 %), maxillary constriction (56.3 %), and taurodontism (53.8 %) were common among patients with MPS VI. Newly recognized oral findings found in our study included taurodontism, long tooth roots, abnormal frenum, missing teeth, supernumerary teeth, and microdontia. Two patients who started ERT prior to 3 years old did not develope anterior open bite and one of them had mildly affected mandibular condyles. CONCLUSION: Our study provides the most comprehensive study of oral manifestations in patients with MPS VI. Receiving ERT at very young ages may lessen craniofacial malformations including hypoplasic mandibular condyles and anterior open bite. Oral manifestations can be used as diagnostic features for MPS VI prior to assessing leukocyte ARSB activity or urinary excretion of dermatan sulfate.


Assuntos
Doenças da Boca/diagnóstico , Doenças da Boca/patologia , Mucopolissacaridose VI/diagnóstico , Mucopolissacaridose VI/patologia , Adolescente , Criança , Pré-Escolar , Terapia de Reposição de Enzimas/métodos , Feminino , Humanos , Lactente , Masculino , Mucopolissacaridose VI/tratamento farmacológico , Adulto Jovem
4.
OMICS ; 28(7): 324-346, 2024 07.
Artigo em Inglês | MEDLINE | ID: mdl-38986083

RESUMO

Congenital heart defects (CHDs) are most prevalent cardiac defects that occur at birth, leading to significant neonatal mortality and morbidity, especially in the developing nations. Among the CHDs, conotruncal heart defects (CTDs) are particularly noteworthy, comprising a significant portion of congenital cardiac anomalies. While advances in imaging and surgical techniques have improved the diagnosis, prognosis, and management of CTDs, their molecular genetics and genomic substrates remain incompletely understood. This expert review covers the recent advances from January 2016 onward and examines the complexities surrounding the genetic etiologies, prevalence, embryology, diagnosis, and clinical management of CTDs. We also emphasize the known copy number variants and single nucleotide variants associated with CTDs, along with the current planetary health research efforts aimed at CTDs in large cohort studies. In all, this comprehensive narrative review of molecular genetics and genomics research and innovation on CTDs draws from and highlights selected works from around the world and offers new ideas for advances in CTD diagnosis, precision medicine interventions, and accurate assessment of prognosis and recurrence risks.


Assuntos
Genômica , Cardiopatias Congênitas , Humanos , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/diagnóstico , Genômica/métodos , Variações do Número de Cópias de DNA/genética , Polimorfismo de Nucleotídeo Único , Prognóstico
5.
Clin Dysmorphol ; 30(1): 6-9, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33038107

RESUMO

GM1 gangliosidosis is a lysosomal storage disorder, characterized by psychomotor deterioration, visceromegaly, facial coarseness, retinal cherry-red spots, and skeletal abnormalities. We report six unrelated patients with GM1 gangliosidosis with extensive Mongolian spots on the trunk and extremities that provided clue to clinical diagnosis. All patients exhibited psychomotor delay, coarse facies, hepatosplenomegaly, hypotonia, and dysostosis multiplex. Four patients had retinal cherry-red spots. The condition was confirmed by identification of very low activities of beta-galactosidase enzyme in peripheral leukocytes and biallelic pathogenic variants in the GLB1 gene. We identified one novel (c.1479G>T) and two known (c.75 + 2dup and c.1369C>T) pathogenic variants in homozygous state in them. Our work ascertains extensive Mongolian spots as a diagnostic handle for early recognition of GM1 gangliosidosis. Though a known feature of GM1 gangliosidosis, considerable variation in the prevalence and ethnic differences are observed. This report illustrates the Mongolian spots pictorially in Indian patients.


Assuntos
Gangliosidose GM1/diagnóstico , Gangliosidose GM1/genética , Mancha Mongólica/diagnóstico , Mancha Mongólica/genética , Mutação , Fenótipo , Alelos , Estudos de Associação Genética , Predisposição Genética para Doença , Homozigoto , Humanos , Índia , Leucócitos/metabolismo , beta-Galactosidase/genética , beta-Galactosidase/metabolismo
6.
J Integr Bioinform ; 18(1): 27-43, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33761582

RESUMO

The pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people and claimed thousands of lives. Starting in China, it is arguably the most precipitous global health calamity of modern times. The entire world has rocked back to fight against the disease and the COVID-19 vaccine is the prime weapon. Even though the conventional vaccine development pipeline usually takes more than a decade, the escalating daily death rates due to COVID-19 infections have resulted in the development of fast-track strategies to bring in the vaccine under a year's time. Governments, companies, and universities have networked to pool resources and have come up with a number of vaccine candidates. Also, international consortia have emerged to address the distribution of successful candidates. Herein, we summarize these unprecedented developments in vaccine science and discuss the types of COVID-19 vaccines, their developmental strategies, and their roles as well as their limitations.


Assuntos
Vacinas contra COVID-19 , COVID-19/prevenção & controle , Pandemias/prevenção & controle , Humanos , SARS-CoV-2/fisiologia , Vacinas
7.
Bone ; 120: 204-211, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30408610

RESUMO

Genetic heterogeneity, high burden and the paucity of genetic testing for rare diseases challenge genomic healthcare for these disorders in India. Here we report our experience over the past decade, of establishing the genomic evaluation of skeletal dysplasia at a tertiary university hospital in India. Research or clinical genomic testing was carried out by Sanger sequencing and next-generation sequencing. Close national and international collaborations aided phenotyping and genotyping. We report 508 families (557 affected individuals) with the definitive molecular diagnosis of skeletal dysplasia. Dysostoses multiplex (n = 196), genetic inflammatory/rheumatoid-like osteoarthropathies (n = 114) and osteogenesis imperfecta and decreased bone density (n = 58) were the most common diagnoses. We enumerate the processes, clinical diagnoses and causal variants in the cohort with 48 novel variants in 21 genes. We summarize scientific contributions of the center to the description of clinical and mutation profiles and discovery of new phenotypes and genetic etiology. Our study illustrates the establishment and application of genomic testing tools for genetic disorders of skeleton in a large cohort. We believe this could be a model to emulate for other developing genetic centers.


Assuntos
Osteocondrodisplasias/genética , Osteocondrodisplasias/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Genótipo , Humanos , Índia , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fenótipo , Reprodutibilidade dos Testes , Adulto Jovem
8.
Gene ; 599: 19-27, 2017 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-27826022

RESUMO

MPS VI is an autosomal recessive disorder which occurs due to the deficiency of N-acetyl galactosamine-4-sulfatase (Arylsulfatase B - ARSB) involved in catabolism of dermatan sulfate resulting from disease-causing variations in the ARSB gene. Human Gene Mutation Database (HGMD) search revealed 200 different mutations in ARSB worldwide. In the present study we carried out molecular and functional analyses to characterize the mutations reported by us in Indian population. Mutation analysis of 19 MPS VI patients revealed presence of a total of 15 different mutations of which twelve were novel [p.Asp53Asn (c.157G>A; p.D53N), p.Leu98Arg (c.293T>G; p.L98R), p.Tyr103Serfs*9 (c.306_312delCTACCAG+146del; p.Y103Sfs*9), p.Phe166Leufs*18 (c.496delT; p.F166Lfs*18), p.Ile220Serfs*5 (c.659_660delTA; p.I220Sfs*5), p.Ile350Phe (c.1048A>T; p.I350F), p.Trp353* (c.1059G>A; p.W353*), p.His393Arg (c.1178A>G; p.H393R), p.Ser403Tyrfs* (c.1208delC; p.S403Yfs*), p.Pro445Leu (c.1334C>T; p.P445L), p.Trp450Leu (c.1349G>T; p.W450L) and p.Trp450Cys (c.1350G>C; p.W450C)] and three were known mutations [p.Asp54Asn (c.160G>A; p.D54N), p.Ala237Asp (c.710C>A; p.A237D) and p.Ser320Arg (c.960C>G; p.S320R)]. Functional characterization using site-directed mutagenesis followed by cell transfection assays, immunoblot, reverse transcriptase PCR and immunofluorescence studies for the putative pathogenic variants detected in our MPS VI patient cohort helped us to confirm the pathogenic potential of the variants in ARSB.


Assuntos
Mucopolissacaridose VI/enzimologia , Mucopolissacaridose VI/genética , Mutação , N-Acetilgalactosamina-4-Sulfatase/genética , N-Acetilgalactosamina-4-Sulfatase/metabolismo , Adolescente , Animais , Sequência de Bases , Células COS , Criança , Pré-Escolar , Chlorocebus aethiops , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Humanos , Índia , Lactente , Masculino , Mucopolissacaridose VI/patologia , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Fenótipo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
9.
BMJ Case Rep ; 20152015 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-25976201

RESUMO

Hunter syndrome is an X linked recessive mucopolysaccharidosis (type II) caused by the deficiency of iduronate 2-sulfatase. This in turn leads to the accumulation of glycosaminoglycans, dermatan and heparan sulfate. The intracellular and extracellular accumulation of these substances lead to multisystemic organ abnormality. It is a rare syndrome with a very low prevalence of 1.3:100,000 male live births. Usual presentation is in early childhood although milder variants have been documented to present at a later age. We present a rare case of Hunter syndrome in a 24-year-old male patient who presented with joint contractures and recent onset hoarseness of voice. X-rays were suggestive of dysostosis multiplex. Clinical diagnosis of Hunter syndrome was confirmed by enzyme assay and further by mutational analysis.


Assuntos
Terapia de Reposição de Enzimas/métodos , Rouquidão/diagnóstico , Iduronato Sulfatase/administração & dosagem , Mucopolissacaridose II/diagnóstico , Adulto , Idade de Início , Eletrocardiografia , Rouquidão/genética , Humanos , Infusões Intravenosas , Masculino , Mucopolissacaridose II/tratamento farmacológico , Mucopolissacaridose II/fisiopatologia
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