TY - JOUR
T1 - Defective ciliogenesis in INPP5E-related Joubert syndrome
AU - Hardee, Isabel
AU - Soldatos, Ariane
AU - Davids, Mariska
AU - Vilboux, Thierry
AU - Toro, Camilo
AU - David, Karen L.
AU - Ferreira, Carlos R.
AU - Nehrebecky, Michele
AU - Snow, Joseph
AU - Thurm, Audrey
AU - Heller, Theo
AU - Macnamara, Ellen F.
AU - Gunay-Aygun, Meral
AU - Zein, Wadih M.
AU - Gahl, William A.
AU - Malicdan, May Christine V.
N1 - Funding Information:
Wethankthepatientsandtheirparentsfortheirparticipationinthisstudy. This work was supported by the Intramural Research Program of the National Human Genome Research Institute and the Common Fund of the NIH Office of the Director. Barbara Pusey and the bioinformatics team at the NIH-UDP, specifically Trevor Frisby and Christopher Adams, provided
Publisher Copyright:
© 2017 Wiley Periodicals, Inc.
PY - 2017/12
Y1 - 2017/12
N2 - Joubert syndrome is a neurodevelopmental disorder, characterized by malformation of the mid and hindbrain leading to the pathognomonic molar tooth appearance of the brainstem and cerebellum on axial MRI. Core clinical manifestations include hypotonia, tachypnea/apnea, ataxia, ocular motor apraxia, and developmental delay of varying degrees. In addition, a subset of patients has retinal dystrophy, chorioretinal colobomas, hepatorenal fibrocystic disease, and polydactyly. Joubert syndrome exhibits genetic heterogeneity, with mutations identified in more than 30 genes, including INPP5E, a gene encoding inositol polyphosphate 5-phosphatase E, which is important in the development and stability of the primary cilium. Here, we report the detailed clinical phenotypes of two sisters with a novel homozygous variant in INPP5E (NM_019892.4: c.1565G>C, NP_063945.2: p.Gly552Ala), expanding the phenotype associated with Joubert syndrome type 1. Expression studies using patient-derived fibroblasts showed changes in mRNA and protein levels. Analysis of fibroblasts from patients revealed that a significant number of cells had shorter or no cilia, indicating defects in ciliogenesis, and cilia maintenance.
AB - Joubert syndrome is a neurodevelopmental disorder, characterized by malformation of the mid and hindbrain leading to the pathognomonic molar tooth appearance of the brainstem and cerebellum on axial MRI. Core clinical manifestations include hypotonia, tachypnea/apnea, ataxia, ocular motor apraxia, and developmental delay of varying degrees. In addition, a subset of patients has retinal dystrophy, chorioretinal colobomas, hepatorenal fibrocystic disease, and polydactyly. Joubert syndrome exhibits genetic heterogeneity, with mutations identified in more than 30 genes, including INPP5E, a gene encoding inositol polyphosphate 5-phosphatase E, which is important in the development and stability of the primary cilium. Here, we report the detailed clinical phenotypes of two sisters with a novel homozygous variant in INPP5E (NM_019892.4: c.1565G>C, NP_063945.2: p.Gly552Ala), expanding the phenotype associated with Joubert syndrome type 1. Expression studies using patient-derived fibroblasts showed changes in mRNA and protein levels. Analysis of fibroblasts from patients revealed that a significant number of cells had shorter or no cilia, indicating defects in ciliogenesis, and cilia maintenance.
KW - INPP5E
KW - Joubert syndrome
KW - ciliopathy
KW - molar-tooth sign
KW - rare disorders
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U2 - 10.1002/ajmg.a.38376
DO - 10.1002/ajmg.a.38376
M3 - Article
C2 - 29052317
AN - SCOPUS:85031705779
SN - 1552-4825
VL - 173
SP - 3231
EP - 3237
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 12
ER -