Two pathogenic mutations located within the 5'-regulatory sequence of the GJB1 gene affecting initiation of transcription and translation.

Kabzińska, Dagmara; Kotruchow, Katarzyna; Ryniewicz, Barbara; Kochański, Andrzej

doi:10.18388/abp.2011_2247

Cited by 15 publications

(10 citation statements)

References 26 publications

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“…11 In table e-2, there is an overview of all mutations in the 5′ and 3′ UTR regions of GJB1 and the corresponding nomenclature based on counting directly from the ATG translation initiation codon, which has been previously used to describe a number of mutations. The previously reported mutations 9,12–15 c.-103C>T and c.-17G>A were detected in 2 (3 and 7) and 4 unrelated families (1, 2, 4, and 9), respectively, and segregated with the phenotype in all family members tested. Three novel mutations were identified: c.-146-90_-146-89insT in family 8, c.-17+1G>T in family 6, and c.*15C>T in families 5 and 10.…”

Section: Resultsmentioning

confidence: 68%

Mutations in noncoding regions of GJB1 are a major cause of X-linked CMT

Tomaselli¹,

Rossor²,

Horga³

et al. 2017

Neurology

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Objective:To determine the prevalence and clinical and genetic characteristics of patients with X-linked Charcot-Marie-Tooth disease (CMT) due to mutations in noncoding regions of the gap junction β-1 gene (GJB1).Methods:Mutations were identified by bidirectional Sanger sequence analysis of the 595 bases of the upstream promoter region, and 25 bases of the 3′ untranslated region (UTR) sequence in patients in whom mutations in the coding region had been excluded. Clinical and neurophysiologic data were retrospectively collected.Results:Five mutations were detected in 25 individuals from 10 kindreds representing 11.4% of all cases of CMTX1 diagnosed in our neurogenetics laboratory between 1996 and 2016. Four pathogenic mutations, c.-17G>A, c.-17+1G>T, c.-103C>T, and c.-146-90_146-89insT were detected in the 5′UTR. A novel mutation, c.*15C>T, was detected in the 3′ UTR of GJB1 in 2 unrelated families with CMTX1 and is the first pathogenic mutation in the 3′UTR of any myelin-associated CMT gene. Mutations segregated with the phenotype, were at sites predicted to be pathogenic, and were not present in the normal population.Conclusions:Mutations in noncoding DNA are a major cause of CMTX1 and highlight the importance of mutations in noncoding DNA in human disease. Next-generation sequencing platforms for use in inherited neuropathy should therefore include coverage of these regions.

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Section: Resultsmentioning

confidence: 68%

Mutations in noncoding regions of GJB1 are a major cause of X-linked CMT

Tomaselli¹,

Rossor²,

Horga³

et al. 2017

Neurology

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“…A CMTX é definida como uma neuropatia hereditária sensitiva e motora de herança mendeliana ligada ao cromossomo X, caracterizada por fraqueza, atrofia muscular distal progressiva, deformidades esqueléticas ("pes cavus" e dedos em martelo), arreflexia e anormalidades sensitivas variáveis. (BONE et al, 1997;KABZINSKA et al, 2011). Isto provavelmente ocorre devido ao fenômeno da lionização, na qual um dos cromossomos X da mulher é inativado aleatoriamente durante o desenvolvimento embrionário (ALBERTS et al, 2002).…”

Section: Charcot-marie-tooth Ligada Ao Cromossomo X (Cmtx)unclassified

“…Pelo fato de possuir duas regiões promotoras o gene GJB1 é capaz de codificar duas variantes da mesma proteína (Cx32). O transcrito da variante 2 é regulado pela região promotora P1 e está presente em células do fígado, pâncreas, oócitos e células tronco embrionárias (KABZINSKA et al, 2011). No sistema nervoso periférico, mais especificamente nas células de Schwann, o transcrito da Cx32 expresso é o da variante 1, iniciado principalmente pela região promotora P2.…”

Section: Regulação Da Expressão Da Cx32 Pelo Gene Gjb1unclassified

“…Fato este que poderia explicar, em tese, porque os sintomas relacionados ao SNC nos pacientes de CMTX1 vão de leves a moderados e até mesmo ausentes (KABZINSKA et al, 2011;MURPHY et al, 2011).…”

Section: Regulação Da Expressão Da Cx32 Pelo Gene Gjb1unclassified

“…No caso da neuropatia de "Charcot-Marie-Tooth" (CMT), pouco ainda se sabe sobre os fenótipos resultantes de mutações localizadas em sequencias regulatórias dos genes relacionados a doença. Por exemplo, na CMT ligada ao cromossomo X do tipo 1 (CMTX1), que é causada por mutações no gene GJB1 que codifica para a proteína canal conexina 32, apenas 0.01% das mutações já detectadas no gene estão presentes na região 5' UTR (Untranslated Region) (KABZINSKA et al, 2011). Objetivos: Em vista disso, o propósito deste estudo foi a analise mutacional da região não codificante 5' UTR e região promotora P2 do gene GJB1.…”

Section: Introductionunclassified

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Analise mutacional das regiões não codificantes 5\'UTR e promotora P2 do gene GJB1 em indivíduos acometidos por CMTX do tipo 1

Lorena¹

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Pathological Mutations in 5′ Untranslated Regions of Human Genes

Chatterjee

Rao

Pal

2017

Encyclopedia of Life Sciences

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The 5′ untranslated region (5′‐UTR) of a messenger ribonucleic acid (mRNA) plays a critical role in translational regulation by influencing mRNA stability and translation efficiency. Functional elements in the 5′‐UTR such as internal ribosome entry site (IRES), upstream open‐reading frames (uORFs) and iron‐responsive element (IRE) serve to fine tune protein expression in response to cellular requirement. Genetic variations such as mutations and single nucleotide polymorphisms (SNPs) in the 5′‐UTR are associated with a number of human diseases and increased susceptibility to diseases. Such pathological variations disrupt the motifs at the 5′‐UTR and cause diseases such as X‐linked Charcot‐Marie‐Tooth (CMTX) disease, multiple myeloma, hereditary hyperferritinaemia/cataract syndrome (HHCS), familial predisposition to melanoma, Marie Unna hereditary hypotrichosis (MUHH), oesophageal cancer and many others. Genetic and molecular profiling of many diseases has shown that a holistic approach including the UTRs in regular diagnostic deoxyribonucleic acid (DNA) screening would aid in better disease profiling and disease management. Key Concepts 5′ Untranslated regions (UTRs) are noncoding regions of messenger ribonucleic acids (mRNAs). The 5′‐UTR is delimited by transcriptional initiation site at 5′ end and the physiological start codon (AUG) at the 3′ end. Motifs such as internal ribosome entry site (IRES), upstream open‐reading frames (uORFs), iron‐responsive element (IRE) and others are involved in mRNA stability and translational control. mRNAs encoding regulatory proteins need to be strongly and precisely regulated. These mRNAs are often endowed with longer than average 5′‐UTR, uORFs and stable secondary structures that regulate their translation efficiency. Mutations are changes in the DNA/genes of an organism, which are heritable. Mutations that disrupt the functional elements of the 5′‐UTR are often associated with diseases. Single nucleotide polymorphisms (SNPs) in the 5′‐UTR are associated with drug response and disease risk in an individual.

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Two pathogenic mutations located within the 5'-regulatory sequence of the GJB1 gene affecting initiation of transcription and translation.

Cited by 15 publications

References 26 publications

Mutations in noncoding regions of GJB1 are a major cause of X-linked CMT

Mutations in noncoding regions of GJB1 are a major cause of X-linked CMT

Analise mutacional das regiões não codificantes 5\'UTR e promotora P2 do gene GJB1 em indivíduos acometidos por CMTX do tipo 1

Pathological Mutations in 5′ Untranslated Regions of Human Genes

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