title: Phenotypic and functional consequences of haploinsufficiency of genes from exocyst and retinoic acid pathway due to a recurrent microdeletion of 2p13.2.
abstract: BACKGROUND
  Rare, recurrent genomic imbalances facilitate the association of genotype with abnormalities at the "whole body" level. However, at the cellular level, the functional consequences of recurrent genomic abnormalities and how they can be linked to the phenotype are much less investigated.
  
  
  RESULTS
  We report an example of a functional analysis of two genes from a new, overlapping microdeletion of 2p13.2 region (from 72,140,702-72,924,626). The subjects shared intellectual disability (ID), language delay, hyperactivity, facial asymmetry, ear malformations, and vertebral and/or craniofacial abnormalities. The overlapping region included two genes, EXOC6B and CYP26B1, which are involved in exocytosis/Notch signaling and retinoic acid (RA) metabolism, respectively, and are of critical importance for early morphogenesis, symmetry as well as craniofacial, skeleton and brain development. The abnormal function of EXOC6B was documented in patient lymphoblasts by its reduced expression and with perturbed expression of Notch signaling pathway genes HES1 and RBPJ, previously noted to be the consequence of EXOC6B dysfunction in animal and cell line models. Similarly, the function of CYP26B1 was affected by the deletion since the retinoic acid induced expression of this gene in patient lymphoblasts was significantly lower compared to controls (8% of controls).
  
  
  CONCLUSIONS
  Haploinsufficiency of CYP26B1 and EXOC6B genes involved in retinoic acid and exocyst/Notch signaling pathways, respectively, has not been reported previously in humans. The developmental anomalies and phenotypic features of our subjects are in keeping with the dysfunction of these genes, considering their known role. Documenting their dysfunction at the cellular level in patient cells enhanced our understanding of biological processes which contribute to the clinical phenotype.
authors.affiliation: Child and Family Research Institute, Department of Pathology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jiadi
authors.initials: J
authors.lastname: Wen
authors.forename: Fátima
authors.initials: F
authors.lastname: Lopes
authors.forename: Gabriela
authors.initials: G
authors.lastname: Soares
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Farrell
authors.forename: Cara
authors.initials: C
authors.lastname: Nelson
authors.forename: Ying
authors.initials: Y
authors.lastname: Qiao
authors.forename: Sally
authors.initials: S
authors.lastname: Martell
authors.forename: Chansonette
authors.initials: C
authors.lastname: Badukke
authors.forename: Carlos
authors.initials: C
authors.lastname: Bessa
authors.forename: Bauke
authors.initials: B
authors.lastname: Ylstra
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lewis
authors.forename: Nina
authors.initials: N
authors.lastname: Isoherranen
authors.forename: Patricia
authors.initials: P
authors.lastname: Maciel
authors.forename: Evica
authors.initials: E
authors.lastname: Rajcan-Separovic
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000293:Adolescent; D001848:Bone Diseases, Developmental / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D002648:Child; D002872:Chromosome Deletion; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000473:pathology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D002658:Developmental Disabilities / Q000235:genetics* / Q000473:pathology; D005089:Exocytosis / Q000235:genetics; D019204:GTP-Binding Proteins / Q000235:genetics; D005838:Genotype; D057895:Haploinsufficiency; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D000072516:Retinoic Acid 4-Hydroxylase; D014212:Tretinoin / Q000378:metabolism
chemical_list: C489222:EXOC6B protein, human; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; C000607079:CYP26B1 protein, human; D000072516:Retinoic Acid 4-Hydroxylase; D019204:GTP-Binding Proteins