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  1. Article ; Online: Endosomal trafficking defects in patient cells with KIAA1109 biallelic variants

    Megan S. Kane / Callie J. Diamonstein / Natalie Hauser / John F. Deeken / John E. Niederhuber / Thierry Vilboux

    Genes and Diseases, Vol 6, Iss 1, Pp 56-

    2019  Volume 67

    Abstract: The uncharacterized gene KIAA1109 has recently been associated with a congenital neurological malformation disorder that variably presents with arthrogryposis, craniofacial and/or cardiac abnormalities. We have identified two additional patients with ... ...

    Abstract The uncharacterized gene KIAA1109 has recently been associated with a congenital neurological malformation disorder that variably presents with arthrogryposis, craniofacial and/or cardiac abnormalities. We have identified two additional patients with compound heterozygous KIAA1109 variants presenting with the same neurological malformations. The mechanism whereby KIAA1109 loss of function causes this spectrum of disorders was the primary focus of our studies. We hypothesized that KIAA1109 function could be conserved relative to the fly gene tweek and examined endocytosis and endosome recycling in patient fibroblasts. Furthermore, we examined the structure of the cytoskeleton and cilia based on functional overlap with endocytosis and several known etiologies for neuronal migration disorders. Utilizing primary dermal fibroblasts from one patient and a healthy donor, we performed immunofluorescence and endocytosis assays to examine the endosomal, cytoskeletal, and ciliary cellular phenotypes. We found notable abnormalities in endosomal trafficking and endosome recycling pathways. We also observed changes in the actin cytoskeleton and cilia structural dynamics. We conclude that the function of KIAA1109 in humans may indeed overlap with the function of the Drosophila ortholog, resulting in perturbations to endosomal trafficking and the actin cytoskeleton. These alterations have ripple effects, altering many pathways that are critical for proper neuronal migration and embryonic development. Keywords: Cilia, Endocytosis, KIAA1109, Neurological malformation, Vesicular trafficking
    Keywords Medicine (General) ; R5-920 ; Genetics ; QH426-470
    Subject code 612
    Language English
    Publishing date 2019-03-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Differences in maternal gene expression in Cesarean section delivery compared with vaginal delivery

    Prachi Kothiyal / Keriann Schulkers / Xinyue Liu / Sahel Hazrati / Thierry Vilboux / Luis M. Gomez / Kathi Huddleston / Wendy S. W. Wong / John E. Niederhuber / Thomas P. Conrads / G. Larry Maxwell / Suchitra K. Hourigan

    Scientific Reports, Vol 10, Iss 1, Pp 1-

    2020  Volume 9

    Abstract: Abstract Cesarean section (CS) is recognized as being a shared environmental risk factor associated with chronic immune disease. A study of maternal gene expression changes between different delivery modes can add to our understanding of how CS ... ...

    Abstract Abstract Cesarean section (CS) is recognized as being a shared environmental risk factor associated with chronic immune disease. A study of maternal gene expression changes between different delivery modes can add to our understanding of how CS contributes to disease patterns later in life. We evaluated the association of delivery mode with postpartum gene expression using a cross-sectional study of 324 mothers who delivered full-term (≥ 37 weeks) singletons. Of these, 181 mothers had a vaginal delivery and 143 had a CS delivery (60 with and 83 without labor). Antimicrobial peptides (AMP) were upregulated in vaginal delivery compared to CS with or without labor. Peptidase inhibitor 3 (PI3), a gene in the antimicrobial peptide pathway and known to be involved in antimicrobial and anti-inflammatory activities, showed a twofold increase in vaginal delivery compared to CS with or without labor (adjusted p-value 1.57 × 10–11 and 3.70 × 10–13, respectively). This study evaluates differences in gene expression by delivery mode and provides evidence of antimicrobial peptide upregulation in vaginal delivery compared to CS with or without labor. Further exploration is needed to determine if AMP upregulation provides protection against CS-associated diseases later in life.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2020-10-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Molecular analysis of the Retinoic Acid Induced 1 gene (RAI1) in patients with suspected Smith-Magenis syndrome without the 17p11.2 deletion.

    Thierry Vilboux / Carla Ciccone / Jan K Blancato / Gerald F Cox / Charu Deshpande / Wendy J Introne / William A Gahl / Ann C M Smith / Marjan Huizing

    PLoS ONE, Vol 6, Iss 8, p e

    2011  Volume 22861

    Abstract: Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder characterized by multiple congenital anomalies. The syndrome is primarily ascribed to a ∼3.7 Mb de novo deletion on chromosome 17p11.2. Haploinsufficiency of multiple genes likely ... ...

    Abstract Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder characterized by multiple congenital anomalies. The syndrome is primarily ascribed to a ∼3.7 Mb de novo deletion on chromosome 17p11.2. Haploinsufficiency of multiple genes likely underlies the complex clinical phenotype. RAI1 (Retinoic Acid Induced 1) is recognized as a major gene involved in the SMS phenotype. Extensive genetic and clinical analyses of 36 patients with SMS-like features, but without the 17p11.2 microdeletion, yielded 10 patients with RAI1 variants, including 4 with de novo deleterious mutations, and 6 with novel missense variants, 5 of which were familial. Haplotype analysis showed two major RAI1 haplotypes in our primarily Caucasian cohort; the novel RAI1 variants did not occur in a preferred haplotype. RNA analysis revealed that RAI1 mRNA expression was significantly decreased in cells of patients with the common 17p11.2 deletion, as well as in those with de novo RAI1 variants. Expression levels varied in patients with familial RAI1 variants and in non-17p11.2 deleted patients without identified RAI1 defects. No correlation between SNP haplotype and RAI1 expression was found. Two clinical features, ocular abnormalities and polyembolokoilomania (object insertion), were significantly correlated with decreased RAI1 expression. While not significantly correlated, the presence of hearing loss, seizures, hoarse voice, childhood onset of obesity and specific behavioral aspects and the absence of immunologic abnormalities and cardiovascular or renal structural anomalies, appeared to be specific for the de novo RAI1 subgroup. Recognition of the combination of these features will assist in referral for RAI1 analysis of patients with SMS-like features without detectable microdeletion of 17p11.2. Moreover, RAI1 expression emerged as a genetic target for development of therapeutic interventions for SMS.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616 ; 610
    Language English
    Publishing date 2011-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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