Joubert syndrome: brain and spinal cord malformations in genotyped cases and implications for neurodevelopmental functions of primary cilia

Abstract

Joubert syndrome (JS) is an autosomal recessive ciliopathy characterized by hypotonia, ataxia, abnormal eye movements, and intellectual disability. The brain is malformed, with severe vermian hypoplasia, fourth ventriculomegaly, and "molar tooth" appearance of the cerebral and superior cerebellar peduncles visible as consistent features on neuroimaging. Neuropathological studies, though few, suggest that several other brain and spinal cord structures, such as the dorsal cervicomedullary junction, may also be affected in at least some patients. Genetically, JS is heterogeneous, with mutations in 13 genes accounting for approximately 50% of patients. Here, we compare neuropathologic findings in five subjects with JS, including four with defined mutations in OFD1 (2 siblings), RPGRIP1L, or TCTN2. Characteristic findings in all JS genotypes included vermian hypoplasia, fragmented dentate and spinal trigeminal nuclei, hypoplastic pontine and inferior olivary nuclei, and nondecussation of corticospinal tracts. Other common findings, seen in multiple genotypes but not all subjects, were dorsal cervicomedullary heterotopia, nondecussation of superior cerebellar peduncles, enlarged arcuate nuclei, hypoplastic reticular formation, hypoplastic medial lemnisci, and dorsal spinal cord disorganization. Thus, while JS exhibits significant neuropathologic as well as genetic heterogeneity, no genotype-phenotype correlations are apparent as yet. Our findings suggest that primary cilia are important for neural patterning, progenitor proliferation, cell migration, and axon guidance in the developing human brain and spinal cord.

Joubert syndrome: neuroimaging findings in 110 patients in correlation with cognitive function and genetic cause

“…In three patients (4%), we found nodular brain-isointense tissue between and in direct contact with the cerebral peduncles, matching our previous observations 31. Given the role of primary cilia in controlling cell migration, these lesions most likely represent grey matter heterotopias, although it is not possible to conclude with certainty in the absence of histological confirmation 32 33. The possibility of heterotopic projection of the pyramidal tract into the interpeduncular cistern with interpeduncular white matter heterotopia should be also considered as previously shown in one fetus by Mitter et al 34…”

NudC regulates actin dynamics and ciliogenesis by stabilizing cofilin 1

“…Cilia have been demonstrated to be involved in various developmental processes in vertebrates [5,11,23,24]; therefore, we explored the function of NudC during zebrafish development. Zebrafish NudC shares high homology with human NudC (identity, 72.0%; similarity, 85.0%) and the polyclonal antibodies against human NudC also recognized zebrafish NudC ( Figure 3A).…”

Tectonic Proteins Are Important Players in Non-Motile Ciliopathies

“…A compound heterozygous TCTN2 mutation (c.1117G>A [p.G373R] and c.76delG[p. D26TfsX26] ) contributed to Joubert syndrome in a Caucasian male child who died at 13 months [27]. A homozygous TCTN2 mutation (c.1235-1G>A) was identified in a male patient with postaxial hexadactyly, hypotonia, nystagmus, hyperopia, ataxic gait and typical MTS on MRI [28].…”