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Joubert Syndrome in French Canadians and Identification of Mutations in CEP104
- Source :
- The American Journal of Human Genetics. 97:744-753
- Publication Year :
- 2015
- Publisher :
- Elsevier BV, 2015.
-
Abstract
- Joubert syndrome (JBTS) is a primarily autosomal-recessive disorder characterized by a distinctive mid-hindbrain and cerebellar malformation, oculomotor apraxia, irregular breathing, developmental delay, and ataxia. JBTS is a genetically heterogeneous ciliopathy. We sought to characterize the genetic landscape associated with JBTS in the French Canadian (FC) population. We studied 43 FC JBTS subjects from 35 families by combining targeted and exome sequencing. We identified pathogenic (n = 32 families) or possibly pathogenic (n = 2 families) variants in genes previously associated with JBTS in all of these subjects, except for one. In the latter case, we found a homozygous splice-site mutation (c.735+2T>C) in CEP104. Interestingly, we identified two additional non-FC JBTS subjects with mutations in CEP104; one of these subjects harbors a maternally inherited nonsense mutation (c.496C>T [p.Arg166∗]) and a de novo splice-site mutation (c.2572−2A>G), whereas the other bears a homozygous frameshift mutation (c.1328_1329insT [p.Tyr444fs∗3]) in CEP104. Previous studies have shown that CEP104 moves from the mother centriole to the tip of the primary cilium during ciliogenesis. Knockdown of CEP104 in retinal pigment epithelial (RPE1) cells resulted in severe defects in ciliogenesis. These observations suggest that CEP104 acts early during cilia formation by regulating the conversion of the mother centriole into the cilia basal body. We conclude that disruption of CEP104 causes JBTS. Our study also reveals that the cause of JBTS has been elucidated in the great majority of our FC subjects (33/35 [94%] families), even though JBTS shows substantial locus and allelic heterogeneity in this population.
- Subjects :
- Adult
Male
Canada
Adolescent
Nonsense mutation
Population
Biology
Retina
Joubert syndrome
Frameshift mutation
Young Adult
03 medical and health sciences
0302 clinical medicine
Report
Cerebellum
Ciliogenesis
Genetics
medicine
Humans
Abnormalities, Multiple
Exome
Genetics(clinical)
Cilia
Eye Abnormalities
Child
education
Genetics (clinical)
030304 developmental biology
0303 health sciences
education.field_of_study
Homozygote
Infant, Newborn
High-Throughput Nucleotide Sequencing
Infant
Kidney Diseases, Cystic
Prognosis
medicine.disease
Pedigree
Ciliopathy
Child, Preschool
Mutation
Female
Allelic heterogeneity
Microtubule-Associated Proteins
030217 neurology & neurosurgery
Follow-Up Studies
Subjects
Details
- ISSN :
- 00029297
- Volume :
- 97
- Database :
- OpenAIRE
- Journal :
- The American Journal of Human Genetics
- Accession number :
- edsair.doi.dedup.....da2c33136a3c12d0f278dc35e51feb52