Araştırma Çıktıları

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Author: search.filters.author.Guclu, BulentHas files: No

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    De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus
    (CELL PRESS, 2018-01-01) Furey, Charuta Gavankar; Choi, Jungmin; Jin, Sheng Chih; Zeng, Xue; Timberlake, Andrew T.; Nelson-Williams, Carol; Mansuri, M. Shahid; Lu, Qiongshi; Duran, Daniel; Panchagnula, Shreyas; Allocco, August; Karimy, Jason K.; Khanna, Arjun; Gaillard, Jonathan R.; DeSpenza, Tyrone; Antwi, Prince; Loring, Erin; Butler, William E.; Smith, Edward R.; Warf, Benjamin C.; Strahle, Jennifer M.; Limbrick, David D.; Storm, Phillip B.; Heuer, Gregory; Jackson, Eric M.; Iskandar, Bermans J.; Johnston, James M.; Tikhonova, Irina; Castaldi, Christopher; Lopez-Giraldez, Francesc; Bjornson, Robert D.; Knight, James R.; Bilguvar, Kaya; Mane, Shrikant; Alper, Seth L.; Haider, Shozeb; Guclu, Bulent; Bayri, Yasar; Sahin, Yener; Apuzzo, Michael L. J.; Duncan, Charles C.; DiLuna, Michael L.; Gunel, Murat; Lifton, Richard P.; Kahle, Kristopher T.
    Congenital hydrocephalus (CH), featuring markedly enlarged brain ventricles, is thought to arise from failed cerebrospinal fluid (CSF) homeostasis and is treated with lifelong surgical CSF shunting with substantial morbidity. CH pathogenesis is poorly understood. Exome sequencing of 125 CH trios and 52 additional probands identified three genes with significant burden of rare damaging de novo or transmitted mutations: TRIM71 (p = 2.15 x 10(-7)), SMARCC1 (p = 8.15 x 10(-10)), and PTCH1 (p = 1.06 x 10(-6)). Additionally, two de novo duplications were identified at the SHH locus, encoding the PTCH1 ligand (p = 1.2 x 10(-4)). Together, these probands account for similar to 10\% of studied cases. Strikingly, all four genes are required for neural tube development and regulate ventricular zone neural stem cell fate. These results implicate impaired neurogenesis (rather than active CSF accumulation) in the pathogenesis of a subset of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications.
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    Mutation in MEOX1 gene causes a recessive Klippel-Feil syndrome subtype
    (BIOMED CENTRAL LTD, 2013-01-01) Bayrakli, Fatih; Guclu, Bulent; Yakicier, Cengiz; Balaban, Hatice; Kartal, Ugur; Erguner, Bekir; Sagiroglu, Mahmut Samil; Yuksel, Sirin; Ozturk, Ahmet Rasit; Kazanci, Burak; Ozum, Unal; Kars, Hamit Zafer
    Background: Klippel-Feil syndrome (KFS) is characterized by the developmental failure of the cervical spine and has two dominantly inherited subtypes. Affected individuals who are the children of a consanguineous marriage are extremely rare in the medical literature, but the gene responsible for this recessive trait subtype of KFS has recently been reported. Results: We identified a family with the KFS phenotype in which their parents have a consanguineous marriage. Radiological examinations revealed that they carry fusion defects and numerical abnormalities in the cervical spine, scoliosis, malformations of the cranial base, and Sprengel's deformity. We applied whole genome linkage and whole-exome sequencing analysis to identify the chromosomal locus and gene mutated in this family. Whole genome linkage analysis revealed a significant linkage to chromosome 17q12-q33 with a LOD score of 4.2. Exome sequencing identified the G > A p.Q84X mutation in the MEOX1 gene, which is segregated based on pedigree status. Homozygous MEOX1 mutations have reportedly caused a similar phenotype in knockout mice. Conclusions: Here, we report a truncating mutation in the MEOX1 gene in a KFS family with an autosomal recessive trait. Together with another recently reported study and the knockout mouse model, our results suggest that mutations in MEOX1 cause a recessive KFS phenotype in humans.