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Mirella Filocamo - One of the best experts on this subject based on the ideXlab platform.

  • Expanded spectrum of Pelizaeus–Merzbacher-like disease: literature revision and description of a novel GJC2 mutation in an unusually severe form
    European Journal of Human Genetics, 2013
    Co-Authors: Roberta Biancheri, Eleonora Lamantea, Camillo Rosano, Laura Denegri, Francesca Pinto, Federica Lanza, Mariasavina Severino, Mirella Filocamo
    Abstract:

    Homozygous or compound heterozygous mutations in the GJC2 gene, encoding the gap junction protein connexin47 (Cx47), cause the autosomal recessive hypomyelinating Pelizaeus–Merzbacher-like disease (PMLD1, MIM# 608804). Although clinical and neuroradiological findings resemble those of the classic Pelizaeus–Merzbacher disease, PMLD patients usually show a greater level of cognitive and motor functions. Unpredictably a homozygous missense GJC2 mutation (p.Glu260Lys) was found in a patient presenting with a very severe clinical picture characterised by congenital nystagmus and severe neurological impairment. Also magnetic resonance imaging was unusually severe, showing an abnormal supra- and infratentorial white matter involvement extending to the spinal cord. The novel p.Glu260Lys (c.778G>A) mutation, occurring in a highly conserved motif (SRPT E K) of the Cx47 extracellular loop-2 domain, was predicted, by modelling analysis, to break a ‘salt bridge network’, crucial for a proper connexin–connexin interaction to form a connexon, thus hampering the correct formation of the connexon pore. The same structural analysis, extended to the previously reported missense mutations, predicted that most changes were expected to have less severe impact on protein functions, correlating with the mild PMLD1 form of the patients. Our study expands the spectrum of PMLD1 and provides evidence that the extremely severe clinical and neuroradiological PMLD1 form of our patient likely correlates with the predicted impairment of gap junction channel assembly resulting from the detrimental effect of the new p.Glu260Lys mutant allele on Cx47 protein.

  • Expanded spectrum of Pelizaeus-Merzbacher-like disease: literature revision and description of a novel GJC2 mutation in an unusually severe form
    European journal of human genetics : EJHG, 2012
    Co-Authors: Roberta Biancheri, Eleonora Lamantea, Camillo Rosano, Laura Denegri, Francesca Pinto, Federica Lanza, Mariasavina Severino, Mirella Filocamo
    Abstract:

    Homozygous or compound heterozygous mutations in the GJC2 gene, encoding the gap junction protein connexin47 (Cx47), cause the autosomal recessive hypomyelinating Pelizaeus–Merzbacher-like disease (PMLD1, MIM# 608804). Although clinical and neuroradiological findings resemble those of the classic Pelizaeus–Merzbacher disease, PMLD patients usually show a greater level of cognitive and motor functions. Unpredictably a homozygous missense GJC2 mutation (p.Glu260Lys) was found in a patient presenting with a very severe clinical picture characterised by congenital nystagmus and severe neurological impairment. Also magnetic resonance imaging was unusually severe, showing an abnormal supra- and infratentorial white matter involvement extending to the spinal cord. The novel p.Glu260Lys (c.778G>A) mutation, occurring in a highly conserved motif (SRPTEK) of the Cx47 extracellular loop-2 domain, was predicted, by modelling analysis, to break a ‘salt bridge network', crucial for a proper connexin–connexin interaction to form a connexon, thus hampering the correct formation of the connexon pore. The same structural analysis, extended to the previously reported missense mutations, predicted that most changes were expected to have less severe impact on protein functions, correlating with the mild PMLD1 form of the patients. Our study expands the spectrum of PMLD1 and provides evidence that the extremely severe clinical and neuroradiological PMLD1 form of our patient likely correlates with the predicted impairment of gap junction channel assembly resulting from the detrimental effect of the new p.Glu260Lys mutant allele on Cx47 protein.

Sahar Mansour - One of the best experts on this subject based on the ideXlab platform.

  • A novel mutation in GJA1 causing oculodentodigital syndrome and primary lymphoedema in a three generation family.
    Clinical genetics, 2013
    Co-Authors: G Brice, Pia Ostergaard, Peter S Mortimer, Steve Jeffery, Kristiana Gordon, Sahar Mansour
    Abstract:

    Oculodentodigital syndrome (ODD; OMIM 164200) is a congenital condition with phenotypic features most commonly affecting the face, eyes, dentition and digits. The condition is caused by mutations in the GJA1 gene on chromosome 6. GJA1 codes for connexin 43, a gap junction protein important in providing cell to cell communication and is expressed in lymphatic valves. We present a patient with a clinical and molecular diagnosis of ODD and lower limb lymphoedema. Sanger sequencing of family members confirmed that the missense, p.K206R, GJA1 mutation segregated with the phenotype suggestive of causality. To our knowledge this association has not been reported previously. This is therefore the second connexin gene associated with a lymphoedema phenotype after the recent publication of GJC2 (connexin 47) as a cause of four limb lymphoedema.

  • Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype
    Journal of medical genetics, 2011
    Co-Authors: Pia Ostergaard, Michael A. Simpson, G Brice, Sahar Mansour, Fiona Connell, Alexandros Onoufriadis, A H Child, Jae Hwang, Kamini Kalidas, P Mortimer
    Abstract:

    Background Primary lymphoedema describes a chronic, frequently progressive, failure of lymphatic drainage. This disorder is frequently genetic in origin, and a multigenerational family in which eight individuals developed postnatal lymphoedema of all four limbs was ascertained from the joint Lymphoedema/Genetic clinic at St George’s Hospital. Methods Linkage analysis was used to determine a locus, and exome sequencing was employed to look for causative variants. Results Linkage analysis revealed cosegregation of a 16.1 Mb haplotype on chromosome 1q42 that contained 173 known or predicted genes. Whole exome sequencing in a single affected individual was undertaken, and the search for the causative variant was focused to within the linkage interval. This approach revealed two novel non-synonymous single nucleotide substitutions within the chromosome 1 locus, in NVL and GJC2. NVL and GJC2 were sequenced in an additional cohort of individuals with a similar phenotype and nonsynonymous variants were found in GJC2 in four additional families. Conclusion This report demonstrates the power of exome sequencing efficiently applied to a traditional positional cloning pipeline in disease gene discovery, and suggests that the phenotype produced by GJC2 mutations is predominantly one of 4 limb lymphoedema.

  • Rapid identification of mutations in GJC2 in four limb primary lymphoedema using whole exome sequencing combined with linkage analysis
    Journal of Medical Genetics, 2011
    Co-Authors: Pia Ostergaard, Michael A. Simpson, G Brice, Sahar Mansour, Fiona Connell, Alexandros Onoufriadis, A H Child, Jae Hwang, Kamini Kalidas, Peter S Mortimer
    Abstract:

    Primary lymphoedema describes a chronic, frequently progressive, failure of lymphatic drainage. We ascertained a multigenerational family in which eight individuals developed post natal lymphoedema of all four limbs. Linkage analysis revealed cosegregation of a 16.1Mb haplotype on chromosome 1q42 that contained 173 known or predicted genes. We undertook exome sequencing in a single affected individual and focused the search for the causative variant to within the linkage interval. This approach revealed two novel non-synonymous single nucleotide substitutions within the chromosome 1 locus, in NVL and GJC2. We sequenced NVL and GJC2 in an additional cohort of individuals with similar four limb lymphoedema and found nonsynonymous variants in GJC2 in five additional families. This report demonstrates the power of exome sequencing efficiently applied to a traditional positional cloning pipeline in disease gene discovery.

Pia Ostergaard - One of the best experts on this subject based on the ideXlab platform.

  • A novel mutation in GJA1 causing oculodentodigital syndrome and primary lymphoedema in a three generation family.
    Clinical genetics, 2013
    Co-Authors: G Brice, Pia Ostergaard, Peter S Mortimer, Steve Jeffery, Kristiana Gordon, Sahar Mansour
    Abstract:

    Oculodentodigital syndrome (ODD; OMIM 164200) is a congenital condition with phenotypic features most commonly affecting the face, eyes, dentition and digits. The condition is caused by mutations in the GJA1 gene on chromosome 6. GJA1 codes for connexin 43, a gap junction protein important in providing cell to cell communication and is expressed in lymphatic valves. We present a patient with a clinical and molecular diagnosis of ODD and lower limb lymphoedema. Sanger sequencing of family members confirmed that the missense, p.K206R, GJA1 mutation segregated with the phenotype suggestive of causality. To our knowledge this association has not been reported previously. This is therefore the second connexin gene associated with a lymphoedema phenotype after the recent publication of GJC2 (connexin 47) as a cause of four limb lymphoedema.

  • Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype
    Journal of medical genetics, 2011
    Co-Authors: Pia Ostergaard, Michael A. Simpson, G Brice, Sahar Mansour, Fiona Connell, Alexandros Onoufriadis, A H Child, Jae Hwang, Kamini Kalidas, P Mortimer
    Abstract:

    Background Primary lymphoedema describes a chronic, frequently progressive, failure of lymphatic drainage. This disorder is frequently genetic in origin, and a multigenerational family in which eight individuals developed postnatal lymphoedema of all four limbs was ascertained from the joint Lymphoedema/Genetic clinic at St George’s Hospital. Methods Linkage analysis was used to determine a locus, and exome sequencing was employed to look for causative variants. Results Linkage analysis revealed cosegregation of a 16.1 Mb haplotype on chromosome 1q42 that contained 173 known or predicted genes. Whole exome sequencing in a single affected individual was undertaken, and the search for the causative variant was focused to within the linkage interval. This approach revealed two novel non-synonymous single nucleotide substitutions within the chromosome 1 locus, in NVL and GJC2. NVL and GJC2 were sequenced in an additional cohort of individuals with a similar phenotype and nonsynonymous variants were found in GJC2 in four additional families. Conclusion This report demonstrates the power of exome sequencing efficiently applied to a traditional positional cloning pipeline in disease gene discovery, and suggests that the phenotype produced by GJC2 mutations is predominantly one of 4 limb lymphoedema.

  • Rapid identification of mutations in GJC2 in four limb primary lymphoedema using whole exome sequencing combined with linkage analysis
    Journal of Medical Genetics, 2011
    Co-Authors: Pia Ostergaard, Michael A. Simpson, G Brice, Sahar Mansour, Fiona Connell, Alexandros Onoufriadis, A H Child, Jae Hwang, Kamini Kalidas, Peter S Mortimer
    Abstract:

    Primary lymphoedema describes a chronic, frequently progressive, failure of lymphatic drainage. We ascertained a multigenerational family in which eight individuals developed post natal lymphoedema of all four limbs. Linkage analysis revealed cosegregation of a 16.1Mb haplotype on chromosome 1q42 that contained 173 known or predicted genes. We undertook exome sequencing in a single affected individual and focused the search for the causative variant to within the linkage interval. This approach revealed two novel non-synonymous single nucleotide substitutions within the chromosome 1 locus, in NVL and GJC2. We sequenced NVL and GJC2 in an additional cohort of individuals with similar four limb lymphoedema and found nonsynonymous variants in GJC2 in five additional families. This report demonstrates the power of exome sequencing efficiently applied to a traditional positional cloning pipeline in disease gene discovery.

Roberta Biancheri - One of the best experts on this subject based on the ideXlab platform.

  • Expanded spectrum of Pelizaeus–Merzbacher-like disease: literature revision and description of a novel GJC2 mutation in an unusually severe form
    European Journal of Human Genetics, 2013
    Co-Authors: Roberta Biancheri, Eleonora Lamantea, Camillo Rosano, Laura Denegri, Francesca Pinto, Federica Lanza, Mariasavina Severino, Mirella Filocamo
    Abstract:

    Homozygous or compound heterozygous mutations in the GJC2 gene, encoding the gap junction protein connexin47 (Cx47), cause the autosomal recessive hypomyelinating Pelizaeus–Merzbacher-like disease (PMLD1, MIM# 608804). Although clinical and neuroradiological findings resemble those of the classic Pelizaeus–Merzbacher disease, PMLD patients usually show a greater level of cognitive and motor functions. Unpredictably a homozygous missense GJC2 mutation (p.Glu260Lys) was found in a patient presenting with a very severe clinical picture characterised by congenital nystagmus and severe neurological impairment. Also magnetic resonance imaging was unusually severe, showing an abnormal supra- and infratentorial white matter involvement extending to the spinal cord. The novel p.Glu260Lys (c.778G>A) mutation, occurring in a highly conserved motif (SRPT E K) of the Cx47 extracellular loop-2 domain, was predicted, by modelling analysis, to break a ‘salt bridge network’, crucial for a proper connexin–connexin interaction to form a connexon, thus hampering the correct formation of the connexon pore. The same structural analysis, extended to the previously reported missense mutations, predicted that most changes were expected to have less severe impact on protein functions, correlating with the mild PMLD1 form of the patients. Our study expands the spectrum of PMLD1 and provides evidence that the extremely severe clinical and neuroradiological PMLD1 form of our patient likely correlates with the predicted impairment of gap junction channel assembly resulting from the detrimental effect of the new p.Glu260Lys mutant allele on Cx47 protein.

  • Expanded spectrum of Pelizaeus-Merzbacher-like disease: literature revision and description of a novel GJC2 mutation in an unusually severe form
    European journal of human genetics : EJHG, 2012
    Co-Authors: Roberta Biancheri, Eleonora Lamantea, Camillo Rosano, Laura Denegri, Francesca Pinto, Federica Lanza, Mariasavina Severino, Mirella Filocamo
    Abstract:

    Homozygous or compound heterozygous mutations in the GJC2 gene, encoding the gap junction protein connexin47 (Cx47), cause the autosomal recessive hypomyelinating Pelizaeus–Merzbacher-like disease (PMLD1, MIM# 608804). Although clinical and neuroradiological findings resemble those of the classic Pelizaeus–Merzbacher disease, PMLD patients usually show a greater level of cognitive and motor functions. Unpredictably a homozygous missense GJC2 mutation (p.Glu260Lys) was found in a patient presenting with a very severe clinical picture characterised by congenital nystagmus and severe neurological impairment. Also magnetic resonance imaging was unusually severe, showing an abnormal supra- and infratentorial white matter involvement extending to the spinal cord. The novel p.Glu260Lys (c.778G>A) mutation, occurring in a highly conserved motif (SRPTEK) of the Cx47 extracellular loop-2 domain, was predicted, by modelling analysis, to break a ‘salt bridge network', crucial for a proper connexin–connexin interaction to form a connexon, thus hampering the correct formation of the connexon pore. The same structural analysis, extended to the previously reported missense mutations, predicted that most changes were expected to have less severe impact on protein functions, correlating with the mild PMLD1 form of the patients. Our study expands the spectrum of PMLD1 and provides evidence that the extremely severe clinical and neuroradiological PMLD1 form of our patient likely correlates with the predicted impairment of gap junction channel assembly resulting from the detrimental effect of the new p.Glu260Lys mutant allele on Cx47 protein.

Peter S Mortimer - One of the best experts on this subject based on the ideXlab platform.

  • A novel mutation in GJA1 causing oculodentodigital syndrome and primary lymphoedema in a three generation family.
    Clinical genetics, 2013
    Co-Authors: G Brice, Pia Ostergaard, Peter S Mortimer, Steve Jeffery, Kristiana Gordon, Sahar Mansour
    Abstract:

    Oculodentodigital syndrome (ODD; OMIM 164200) is a congenital condition with phenotypic features most commonly affecting the face, eyes, dentition and digits. The condition is caused by mutations in the GJA1 gene on chromosome 6. GJA1 codes for connexin 43, a gap junction protein important in providing cell to cell communication and is expressed in lymphatic valves. We present a patient with a clinical and molecular diagnosis of ODD and lower limb lymphoedema. Sanger sequencing of family members confirmed that the missense, p.K206R, GJA1 mutation segregated with the phenotype suggestive of causality. To our knowledge this association has not been reported previously. This is therefore the second connexin gene associated with a lymphoedema phenotype after the recent publication of GJC2 (connexin 47) as a cause of four limb lymphoedema.

  • Rapid identification of mutations in GJC2 in four limb primary lymphoedema using whole exome sequencing combined with linkage analysis
    Journal of Medical Genetics, 2011
    Co-Authors: Pia Ostergaard, Michael A. Simpson, G Brice, Sahar Mansour, Fiona Connell, Alexandros Onoufriadis, A H Child, Jae Hwang, Kamini Kalidas, Peter S Mortimer
    Abstract:

    Primary lymphoedema describes a chronic, frequently progressive, failure of lymphatic drainage. We ascertained a multigenerational family in which eight individuals developed post natal lymphoedema of all four limbs. Linkage analysis revealed cosegregation of a 16.1Mb haplotype on chromosome 1q42 that contained 173 known or predicted genes. We undertook exome sequencing in a single affected individual and focused the search for the causative variant to within the linkage interval. This approach revealed two novel non-synonymous single nucleotide substitutions within the chromosome 1 locus, in NVL and GJC2. We sequenced NVL and GJC2 in an additional cohort of individuals with similar four limb lymphoedema and found nonsynonymous variants in GJC2 in five additional families. This report demonstrates the power of exome sequencing efficiently applied to a traditional positional cloning pipeline in disease gene discovery.