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Yanick J Crow - One of the best experts on this subject based on the ideXlab platform.

  • striking intrafamilial phenotypic variability in aicardi goutieres syndrome associated with the recurrent asian founder mutation in rnaseh2c
    American Journal of Medical Genetics Part A, 2013
    Co-Authors: Julie Vogt, Yanick J Crow, Shakti Agrawal, Zala Ibrahim, Taunton R Southwood, Sunny Philip, Lesley Macpherson, Malini V Bhole, Christine Oley
    Abstract:

    Aicardi-Gouti�res syndrome (AGS) is an encephalopathy of early childhood which is most commonly inherited as an autosomal recessive trait. The disorder demonstrates significant genetic heterogeneity with causative mutations in five genes identified to date. Although most patients with AGS experience a severe neonatal or infantile presentation, poor neurodevelopmental outcome and reduced survival, clinical variability in the onset and severity of the condition is being increasingly recognized. A later presentation with a more variable effect on development, morbidity and mortality has been particularly observed in association with mutations in SAMHD1 and RNASEH2B. In contrast, the recurrent c.205C > T (p.R69W) RNASEH2C Asian founder mutation has previously only been identified in children with a severe AGS phenotype. Here, to our knowledge, we present the first report of marked phenotypic variability in siblings both harboring this founder mutation in the homozygous state. In this family, one female child had a severe AGS phenotype with an onset in infancy and profound developmental delay, whilst an older sister was of completely normal intellect with a normal head circumference and was only diagnosed because of the presence of chilblains and a mild hemiplegia. An appreciation of intrafamilial phenotypic expression is important in the counseling of families considering prenatal diagnosis, and may also be relevant to the assessment of efficacy in future clinical trials. In addition, marked phenotypic variation raises the possibility that more mildly affected patients are not currently identified.

  • samhd1 is a nucleic acid binding protein that is mislocalized due to aicardi goutieres syndrome associated mutations
    Human Mutation, 2012
    Co-Authors: Adriana Goncalves, Evren Karayel, Gillian I Rice, Yanick J Crow, Giulio Supertifurga, Keiryn L Bennett, Tilmann Burckstummer
    Abstract:

    Aicardi-Gouti�res syndrome (AGS) is a rare inherited autoimmune disease caused by mutations in genes encoding the RNase H2 subunits A, B, and C; the DNase three prime repair exonuclease 1 (TREX1); and sterile alpha motif (SAM) domain and HD domain-containing protein 1 (SAMHD1). Using unbiased affinity purification coupled to protein mass spectrometry, we identify SAMHD1 as a nucleic-acid-binding protein displaying a preference for RNA over DNA. In contrast to TREX1 and the RNase H2 complex, SAMHD1 has no obvious nuclease activity. In addition, interrogating truncation mutants of SAMHD1 observed in AGS patients, we map the nucleic-acid-binding domain to residues 164-442, thus overlapping with the HD domain. Furthermore, we show that although wild-type SAMHD1 displays almost exclusive nuclear localization, 11 of 12 SAMHD1 mutants show at least partial mislocalization to the cytosol. Overall, these data suggest that SAMHD1 has a role in the nucleus that, if disrupted by mutation, leads to cytosolic accumulation of SAMHD1 and autoimmune disease.

  • familial aicardi goutieres syndrome due to samhd1 mutations is associated with chronic arthropathy and contractures
    American Journal of Medical Genetics Part A, 2010
    Co-Authors: Russell C Dale, Gillian I Rice, Hannah Gornall, Davinder Singhgrewal, Melanie Alcausin, Yanick J Crow
    Abstract:

    We report on two siblings doubly heterozygous for null mutations in the recently identified AGS5 gene SAMHD1. The older female child showed mild intellectual disability with microcephaly. Her brother demonstrated a significant spastic paraparesis with normal intellect and head size. Both children had an unclassified chronic inflammatory skin condition with chilblains, and recurrent mouth ulcers. One child had a chronic progressive deforming arthropathy of the small and large joints, with secondary contractures. This family illustrate the remarkable phenotypic diversity accruing from mutations in genes associated with Aicardi-Gouti�res syndrome (AGS). The association of arthropathy with SAMHD1 mutations highlights a phenotypic overlap of AGS with familial autoinflammatory disorders such as chronic infantile neurological cutaneous and articular syndrome (CINCA). This family therefore illustrate the need to consider mutation analysis of SAMHD1 in non-specific inflammatory phenotypes of childhood. We propose that arthropathy with progressive contractures should now be considered part of the spectrum of Aicardi-Gouti�res syndrome because of SAMHD1 mutations.

Gillian I Rice - One of the best experts on this subject based on the ideXlab platform.

  • samhd1 is a nucleic acid binding protein that is mislocalized due to aicardi goutieres syndrome associated mutations
    Human Mutation, 2012
    Co-Authors: Adriana Goncalves, Evren Karayel, Gillian I Rice, Yanick J Crow, Giulio Supertifurga, Keiryn L Bennett, Tilmann Burckstummer
    Abstract:

    Aicardi-Gouti�res syndrome (AGS) is a rare inherited autoimmune disease caused by mutations in genes encoding the RNase H2 subunits A, B, and C; the DNase three prime repair exonuclease 1 (TREX1); and sterile alpha motif (SAM) domain and HD domain-containing protein 1 (SAMHD1). Using unbiased affinity purification coupled to protein mass spectrometry, we identify SAMHD1 as a nucleic-acid-binding protein displaying a preference for RNA over DNA. In contrast to TREX1 and the RNase H2 complex, SAMHD1 has no obvious nuclease activity. In addition, interrogating truncation mutants of SAMHD1 observed in AGS patients, we map the nucleic-acid-binding domain to residues 164-442, thus overlapping with the HD domain. Furthermore, we show that although wild-type SAMHD1 displays almost exclusive nuclear localization, 11 of 12 SAMHD1 mutants show at least partial mislocalization to the cytosol. Overall, these data suggest that SAMHD1 has a role in the nucleus that, if disrupted by mutation, leads to cytosolic accumulation of SAMHD1 and autoimmune disease.

  • familial aicardi goutieres syndrome due to samhd1 mutations is associated with chronic arthropathy and contractures
    American Journal of Medical Genetics Part A, 2010
    Co-Authors: Russell C Dale, Gillian I Rice, Hannah Gornall, Davinder Singhgrewal, Melanie Alcausin, Yanick J Crow
    Abstract:

    We report on two siblings doubly heterozygous for null mutations in the recently identified AGS5 gene SAMHD1. The older female child showed mild intellectual disability with microcephaly. Her brother demonstrated a significant spastic paraparesis with normal intellect and head size. Both children had an unclassified chronic inflammatory skin condition with chilblains, and recurrent mouth ulcers. One child had a chronic progressive deforming arthropathy of the small and large joints, with secondary contractures. This family illustrate the remarkable phenotypic diversity accruing from mutations in genes associated with Aicardi-Gouti�res syndrome (AGS). The association of arthropathy with SAMHD1 mutations highlights a phenotypic overlap of AGS with familial autoinflammatory disorders such as chronic infantile neurological cutaneous and articular syndrome (CINCA). This family therefore illustrate the need to consider mutation analysis of SAMHD1 in non-specific inflammatory phenotypes of childhood. We propose that arthropathy with progressive contractures should now be considered part of the spectrum of Aicardi-Gouti�res syndrome because of SAMHD1 mutations.

Tilmann Burckstummer - One of the best experts on this subject based on the ideXlab platform.

  • samhd1 is a nucleic acid binding protein that is mislocalized due to aicardi goutieres syndrome associated mutations
    Human Mutation, 2012
    Co-Authors: Adriana Goncalves, Evren Karayel, Gillian I Rice, Yanick J Crow, Giulio Supertifurga, Keiryn L Bennett, Tilmann Burckstummer
    Abstract:

    Aicardi-Gouti�res syndrome (AGS) is a rare inherited autoimmune disease caused by mutations in genes encoding the RNase H2 subunits A, B, and C; the DNase three prime repair exonuclease 1 (TREX1); and sterile alpha motif (SAM) domain and HD domain-containing protein 1 (SAMHD1). Using unbiased affinity purification coupled to protein mass spectrometry, we identify SAMHD1 as a nucleic-acid-binding protein displaying a preference for RNA over DNA. In contrast to TREX1 and the RNase H2 complex, SAMHD1 has no obvious nuclease activity. In addition, interrogating truncation mutants of SAMHD1 observed in AGS patients, we map the nucleic-acid-binding domain to residues 164-442, thus overlapping with the HD domain. Furthermore, we show that although wild-type SAMHD1 displays almost exclusive nuclear localization, 11 of 12 SAMHD1 mutants show at least partial mislocalization to the cytosol. Overall, these data suggest that SAMHD1 has a role in the nucleus that, if disrupted by mutation, leads to cytosolic accumulation of SAMHD1 and autoimmune disease.

Russell C Dale - One of the best experts on this subject based on the ideXlab platform.

  • familial aicardi goutieres syndrome due to samhd1 mutations is associated with chronic arthropathy and contractures
    American Journal of Medical Genetics Part A, 2010
    Co-Authors: Russell C Dale, Gillian I Rice, Hannah Gornall, Davinder Singhgrewal, Melanie Alcausin, Yanick J Crow
    Abstract:

    We report on two siblings doubly heterozygous for null mutations in the recently identified AGS5 gene SAMHD1. The older female child showed mild intellectual disability with microcephaly. Her brother demonstrated a significant spastic paraparesis with normal intellect and head size. Both children had an unclassified chronic inflammatory skin condition with chilblains, and recurrent mouth ulcers. One child had a chronic progressive deforming arthropathy of the small and large joints, with secondary contractures. This family illustrate the remarkable phenotypic diversity accruing from mutations in genes associated with Aicardi-Gouti�res syndrome (AGS). The association of arthropathy with SAMHD1 mutations highlights a phenotypic overlap of AGS with familial autoinflammatory disorders such as chronic infantile neurological cutaneous and articular syndrome (CINCA). This family therefore illustrate the need to consider mutation analysis of SAMHD1 in non-specific inflammatory phenotypes of childhood. We propose that arthropathy with progressive contractures should now be considered part of the spectrum of Aicardi-Gouti�res syndrome because of SAMHD1 mutations.

Adriana Goncalves - One of the best experts on this subject based on the ideXlab platform.

  • samhd1 is a nucleic acid binding protein that is mislocalized due to aicardi goutieres syndrome associated mutations
    Human Mutation, 2012
    Co-Authors: Adriana Goncalves, Evren Karayel, Gillian I Rice, Yanick J Crow, Giulio Supertifurga, Keiryn L Bennett, Tilmann Burckstummer
    Abstract:

    Aicardi-Gouti�res syndrome (AGS) is a rare inherited autoimmune disease caused by mutations in genes encoding the RNase H2 subunits A, B, and C; the DNase three prime repair exonuclease 1 (TREX1); and sterile alpha motif (SAM) domain and HD domain-containing protein 1 (SAMHD1). Using unbiased affinity purification coupled to protein mass spectrometry, we identify SAMHD1 as a nucleic-acid-binding protein displaying a preference for RNA over DNA. In contrast to TREX1 and the RNase H2 complex, SAMHD1 has no obvious nuclease activity. In addition, interrogating truncation mutants of SAMHD1 observed in AGS patients, we map the nucleic-acid-binding domain to residues 164-442, thus overlapping with the HD domain. Furthermore, we show that although wild-type SAMHD1 displays almost exclusive nuclear localization, 11 of 12 SAMHD1 mutants show at least partial mislocalization to the cytosol. Overall, these data suggest that SAMHD1 has a role in the nucleus that, if disrupted by mutation, leads to cytosolic accumulation of SAMHD1 and autoimmune disease.