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Publications (3)11.99 Total impact

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    ABSTRACT: Tel2-interacting proteins 1 and 2 (TTI1 and TTI2) physically interact with telomere maintenance 2 (TEL2) to form a conserved trimeric complex called the Triple T complex. This complex is a master regulator of phosphoinositide-3-kinase-related protein kinase (PIKKs) abundance and DNA damage response signaling. Using a combination of autozygosity mapping and high-throughput sequencing in a large consanguineous multiplex family, we found that a missense c.1307T>A/p.I436N mutation in TTI2 causes a human autosomal recessive condition characterized by severe cognitive impairment, microcephaly, behavioral troubles, short stature, skeletal anomalies and facial dysmorphic features. Immunoblotting experiment showed decreased amount of all Triple T complex components in the patient skin fibroblasts. Consistently, a drastically reduced steady-state level of all PIKKs tested were also observed in the patient cells. Combined with previous observations, these findings emphasises the role of the TTI2 gene in the aetiology of intellectual disability (ID) and further support the role of PIKK signaling in brain development and functioning. This article is protected by copyright. All rights reserved.
    Human Mutation 08/2013; · 5.21 Impact Factor
  • Article: Mutation in
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    ABSTRACT: Tel2‐interacting proteins 1 and 2 (TTI1 and TTI2) physically interact with telomere maintenance 2 (TEL2) to form a conserved trimeric complex called the Triple T complex. This complex is a master regulator of phosphoinositide‐3‐kinase‐related protein kinase (PIKKs) abundance and DNA damage response signaling. Using a combination of autozygosity mapping and high‐throughput sequencing in a large consanguineous multiplex family, we found that a missense c.1307T>A/p.I436N mutation in TTI2 causes a human autosomal recessive condition characterized by severe cognitive impairment, microcephaly, behavioral troubles, short stature, skeletal anomalies, and facial dysmorphic features. Immunoblotting experiment showed decreased amount of all Triple T complex components in the patient skin fibroblasts. Consistently, a drastically reduced steady‐state level of all PIKKs tested was also observed in the patient cells. Combined with previous observations, these findings emphasises the role of the TTI2 gene in the etiology of intellectual disability and further support the role of PIKK signaling in brain development and functioning.
    Human Mutation 01/2013; 34(11). · 5.21 Impact Factor
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    ABSTRACT: Homozygous mutations in the ASPM gene are a major cause of autosomal recessive primary microcephaly (MCPH). Here we report on a consanguineous Algerian family in which three out of five children presented with severe microcephaly, simplified cortical gyration, mild to severe mental retardation and low to low-normal birth weight. Given the parental consanguinity with the unaffected parents being third cousins once removed, the most probable pattern of inheritance was autosomal recessive. Linkage and mutational analyses identified compound heterozygous truncating mutations within the ASPM gene segregating with MCPH (c.2389C>T [p.Arg797X] and c.7781_7782delAG [p.Gln2594fsX6]). These results highlight some of the pitfalls of genetic analysis in consanguineous families. They also suggest that low birth weight may be a feature of MCPH, a finding that needs confirmation, and confirm that ASPM mutations are associated with simplified cortical gyration.
    European journal of medical genetics 04/2009; 52(4):180-4. · 1.57 Impact Factor