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    MASP1 Mutations in Patients with Facial, Umbilical, Coccygeal, and Auditory Findings of Carnevale, Malpuech, OSA, and Michels Syndromes
    (Cell Press, 2010) Sirmaci, Asli; Walsh, Tom; Akay, Hatice; Spiliopoulos, Michail; Sakalar, Yildirim Bayezit; Hasanefendioglu-Bayrak, Aylin; Duman, Duygu
    Distinctive facial features consisting of hypertelorism, telecanthus, blepharophimosis blepharoptosis, epicanthus inversus, periumbil seal defects, and skeletal anomalies are seen in autosomal recessive Carnevale, Malpuech, Michels, and oculo skeletal abdominal (OSA) syndromes The gene or genes responsible for these syndromes were heretofore unknown We report on three individuals from two consanguineous Turkish families with findings characteristic of these syndromes including facial dysmorphism periumbilical depression mixed hearing loss, radioulnar synostosis and coccygeal appendage Homozygosity mapping yielded an autozygous region on chromosome 3q27 in both families In one family, whole exome sequencing revealed a missense mutation, MASP1 c 2059G>A (p G687R) that cosegregated with the phenotype In the second family, Sanger sequencing of MASP1 revealed a nonsense mutation, MASP1 c 870G>A (p W290X) that also cosegregated with the phenotype Neither mutation was found in 192 Turkish controls or 1200 controls of various other ancestries MASP1 encodes mannan binding lectin senne protease 1 The two mutations occur in a MASP1 isoform that has been reported to process IGFBP 5 thereby playing a critical role in insulin growth factor availability during craniofacial and muscle development These results implicate mutations of MASP1 as the cause of a human malformation syndrome and demonstrate the involvement of MASP1 in facial, umbilical, and ear development during the embryonic period
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    Mutations in TMC1 contribute significantly to nonsyndromic autosomal recessive sensorineural hearing loss: A report of five novel mutations
    (Elsevier Ireland Ltd, 2009) Sirmaci, Asli; Duman, Duygu; Ozturkmen-Akay, Hatice; Erbek, Seyra; Incesulu, Armagan; Ozturk-Hismi, Burcu; Arici, Z. Serap
    Genome wide homozygosity mapping using Affymetrix 10K arrays revealed the DFNB7/11 locus including the TMC1 gene in 5 of 35 Turkish families with autosomal recessive nonsyndromic severe to profound congenital or prelingual-onset sensorineural hearing loss (SNHL). Additional 51 families were later screened for co-segregation of the locus with the phenotype using microsatellite markers. GJB2 and mtDNA A1555G mutations were negative in probands from each family. Mutation analysis was performed in families showing co-segregation Of autosomal recessive SNHL with haplotypes at the DFNB7/11 locus. A total of six different mutations in seven families were identified, including novel missense alterations, p.G444R (c.1330G > A), p.R445C (c.1333C > T), and p.1677T (c.2030T > C), one novel splice site mutation IVS6+2 T > A (c.64+2T > A), and a novel large deletion ofapproximately 31 kb at the 3' region of the gene including exons 19-24, as well as a previously reported nonsense mutation, p.R34X (c.100C > T). All identified Mutations co-segregated with autosomal recessive SNHL in all families and were not found in Turkish hearing controls. These results expand the mutation spectrum of TMC1 with five novel mutations and provide data for the significant contribution of TMC1 mutations in hearing loss. (c) 2009 Elsevier Ireland Ltd. All rights reserved.