Joubert Syndrome Research Articles

A novel 1.38-kb deletion combined with a single nucleotide variant in KIAA0586 as a cause of Joubert syndrome

BackgroundKIAA0586, also known as Talpid3, plays critical roles in primary cilia formation and hedgehog signaling in humans. Variants in KIAA0586 could cause some different ciliopathies, including Joubert syndrome (JBTS), which is a clinically and genetically heterogeneous group of autosomal recessive neurological disorders.Methods and ResultsA 9-month-old girl was diagnosed as JBTS by the “molar tooth sign” of the mid-brain and global developmental delay. By whole-exome sequencing, we identified a single nucleotide variant c.3303G > A and a 1.38-kb deletion in KIAA0586 in the proband. These two variants of KIAA0586 were consistent with the mode of autosomal recessive inheritance in the family, which was verified using Sanger sequencing.ConclusionsThis finding of a compound heterozygote with a 1.38-kb deletion and c.3303G > A gave a precise genetic diagnosis for the patient, and the novel 1.38-kb deletion also expanded the pathogenic variation spectrum of JBTS caused by KIAA0586.

A novel non-sense variant in the OFD1 gene caused Joubert syndrome.

Background: Joubert syndrome (JBS) is a rare neurodevelopmental disorder associated with progressive renal, liver, and retinal involvement that exhibits heterogeneity in both clinical manifestations and genetic etiology. Therefore, it is difficult to make a definite prenatal diagnosis. Methods: Whole-exome sequencing and Sanger sequencing were performed to screen the causative gene variants in a suspected JBS family. RNA-seq and protein model prediction were performed to clarify the potential pathogenic mechanism. A more comprehensive review of previously reported cases with OFD1 variants is presented and may help to establish a genotype-phenotype. Results: We identified a novel non-sense variant in the OFD1 gene, OFD1 (NM_003611.3): c.2848A>T (p.Lys950Ter). Sanger sequencing confirmed cosegregation among this family. RNA-seq confirmed that partial degradation of mutant transcripts, which was predicted to be caused by the non-sense-mediated mRNA decay (NMD) mechanism, may explain the reduction in the proportion of mutant transcripts. Protein structure prediction of the non-sense variant transcript revealed that this variant may lead to a change in the OFD1 protein structure. Conclusion: The genetic variation spectrum of JBS10 caused by OFD1 was broadened. The novel variants further deepened our insight into the molecular mechanism of the disease.

Clinical features and genetic analysis of two Chinese pedigrees affected with Joubert syndrome

To explore the clinical characteristics and genetic basis of two Chinese pedigrees affected with Joubert syndrome. Clinical data of the two pedigrees was collected. Genomic DNA was extracted from peripheral blood samples and subjected to high-throughput sequencing. Candidate variants were verified by Sanger sequencing. Prenatal diagnosis was carried out for a high-risk fetus from pedigree 2. The proband of pedigree 1 was a fetus at 23+5 weeks gestation, for which both ultrasound and MRI showed "cerebellar vermis malformation" and "molar tooth sign". No apparent abnormality was noted in the fetus after elected abortion. The fetus was found to harbor c.812+3G>T and c.1828G>C compound heterozygous variants of the INPP5E gene, which have been associated with Joubert syndrome type 1. The proband from pedigree 2 had growth retardation, mental deficiency, peculiar facial features, low muscle tone and postaxial polydactyly of right foot. MRI also revealed "cerebellar dysplasia" and "molar tooth sign". The proband was found to harbor c.485C>G and c.1878+1G>A compound heterozygous variants of the ARMC9 gene, which have been associated with Joubert syndrome type 30. Prenatal diagnosis found that the fetus only carried the c.485C>G variant. A healthy infant was born, and no anomalies was found during the follow-up. The compound heterozygous variants of the INPP5E and ARMC9 genes probably underlay the disease in the two pedigrees. Above finding has expanded the spectrum of pathogenic variants underlying Joubert syndrome and provided a basis for genetic counseling and prenatal diagnosis.

Proximity Mapping of CCP6 Reveals Its Association with Centrosome Organization and Cilium Assembly.

The cytosolic carboxypeptidase 6 (CCP6) catalyzes the deglutamylation of polyglutamate side chains, a post-translational modification that affects proteins such as tubulins or nucleosome assembly proteins. CCP6 is involved in several cell processes, such as spermatogenesis, antiviral activity, embryonic development, and pathologies like renal adenocarcinoma. In the present work, the cellular role of CCP6 has been assessed by BioID, a proximity labeling approach for mapping physiologically relevant protein-protein interactions (PPIs) and bait proximal proteins by mass spectrometry. We used HEK 293 cells stably expressing CCP6-BirA* to identify 37 putative interactors of this enzyme. This list of CCP6 proximal proteins displayed enrichment of proteins associated with the centrosome and centriolar satellites, indicating that CCP6 could be present in the pericentriolar material. In addition, we identified cilium assembly-related proteins as putative interactors of CCP6. In addition, the CCP6 proximal partner list included five proteins associated with the Joubert syndrome, a ciliopathy linked to defects in polyglutamylation. Using the proximity ligation assay (PLA), we show that PCM1, PIBF1, and NudC are true CCP6 physical interactors. Therefore, the BioID methodology confirms the location and possible functional role of CCP6 in centrosomes and centrioles, as well as in the formation and maintenance of primary cilia.

Radiological Features of Joubert's Syndrome

AbstractJoubert syndrome (JS) is a rare autosomal recessive disorder. All patients affected by this syndrome presented a characteristic picture of cranial fossa malformations, called “molar tooth sign.” This sign is defined by the presence in axial section at the level of a deck/midbrain, of hypo/dysplasia of the cerebellar vermis, abnormally deep interpeduncular fossa and horizontalized thickened and elongated superior cerebellar peduncles. Although “molar tooth sign” is peculiar of JS, other radiological findings have been also reported in these patients. Here, the authors briefly assumed the principal magnetic resonance imaging findings of JS.

Epilepsy in Joubert Syndrome: A Still Few Explored Matter

AbstractEpilepsy is rarely associated with Joubert's syndrome and related disorders (JSRD), being reported only in 3% of cases. Few patients have been described, moreover, with poor evidences of specific seizures' semiology or standard of practice for pharmacological treatment. Epilepsy is likely to be related to brain malformations in ciliopathies. Beyond the typical hindbrain malformation, the molar tooth sign, other cerebral anomalies variably reported in JSRD, such as generalized polymicrogyria, hamartomas, periventricular nodular heterotopia, and hippocampal defects, have been described. Herein, we aimed to revise the main clinical and etiopathogenetic characteristics of epilepsy associated with JSRD.

A Brief Focus on Joubert Syndrome and Related Acute Complications

AbstractJoubert syndrome (JS) and related disorders are a group of congenital anomalies syndromes in which the obligatory hallmark is the molar tooth sign, a complex midbrain–hindbrain malformation. Moreover, JS may be associated with multiorgan involvement, mainly nephronophthisis, hepatic fibrosis, retinal dystrophy, and other abnormalities with both inter- and intra-familial variability. Therefore, these patients should be followed by both diagnostic protocol and multidisciplinary approach to assess multiorgan involvement. Here, we briefly summarize the possible complications in patients with JS.

An Overview of Genes Involved in the Pure Joubert Syndrome and in Joubert Syndrome-Related Disorders (JSRD)

AbstractJoubert syndrome (JS) is a rare autosomal recessive disease characterized by a peculiar brain malformation, hypotonia, ataxia, developmental delay, abnormal eye movements, and neonatal breathing abnormalities. This picture is often associated with variable multiorgan involvement, mainly of the retina, kidneys and liver, defining a group of conditions termed syndrome and Joubert syndrome-related disorders (JSRD). Currently, more than 30 causative genes have been identified, involved in the development and stability of the primary cilium. Correlations genotype–phenotype are emerging between clinical presentations and mutations in JSRD genes, with implications in terms of molecular diagnosis, prenatal diagnosis, follow-up, and management of mutated patients.

Endocrine manifestations in Joubert syndrome—literature review

<abstract> <p>Joubert syndrome (JS) is a heterogeneously inherited, rare, autosomal recessive disorder characterised by neonatal breathing dysregulation, developmental delay, hypotonia, abnormal eye movements and a distinctive cerebellar and brainstem malformation called the molar tooth sign (MTS). Patients with JS may develop hypothalamic-pituitary dysfunction, leading to growth hormone deficiency, hypothyroidism, adrenal insufficiency and hypogonadism. This review summarizes the screening, diagnosis, and management of these conditions in JS.</p> </abstract>

Joubert Syndrome with Renal and Cerebral Manifestations: A Case Series of Three Siblings

Joubert syndrome is a rare genetic disorder. Marie Joubert made the first official diagnosis of the syndrome in 1969. It is characterised by aberrant neurodevelopment and a complex midbrain-hindbrain malformation which can be seen on the Magnetic Resonance Imaging (MRI) as molar tooth sign. The present case series reports three siblings from a consanguineous marriage. The first child had delayed developmental milestones, ataxia, mental retardation and presented with advanced renal failure and succumbed to uremic complications. The second and third siblings also had similar clinical findings and the diagnosis of Joubert syndrome was confirmed by the presence of molar tooth sign on MRI. The presence of renal failure in them was detected earlier than the first sibling with favourable outcome in both. The characteristic symptoms of Joubert syndrome include developmental delay, intellectual disability, ocular abnormalities, and lack of control over voluntary movements. Each sibling of an affected individual has a 25% chance of developing the disease, a 50% chance of being an asymptomatic carrier, and a 25% chance of being not affected and not being a carrier. Renal involvement occurs in approximately one third of patients. In the present case series, all the siblings were affected by the syndrome and developed renal failure which is extremely rare. Failure to evaluate the renal function in these patients can result in delayed presentation with adverse outcome as seen in the first sibling. The case series highlights the importance of considering this disorder in the differential diagnosis of chronic kidney disease, especially in cases with a family history and other suggestive symptoms and the need for early recognition and management of the disorder, as early intervention and supportive care can improve the patient’s quality of life and prognosis.

Non-syndromic Retinal Degeneration Caused byPathogenic Variants in Joubert Syndrome Genes.

Inherited retinal degenerations (IRDs) are a group of genetic disorders characterized by progressive dysfunction and loss of photoreceptors. IRDs are classified as non-syndromic or syndromic, depending on whether retinal degeneration manifests alone or in combination with other associated symptoms. Joubert syndrome (JBTS) is a genetically and clinically heterogeneous disorder affecting the central nervous system and other organs and tissues, including the neuroretina. To date, 39 genes have been associated with JBTS, a majority of which encode structural or functional components of the primary cilium, a specialized sensory organelle present in most post-mitotic cells, including photoreceptors. The use of whole exome and IRD panel next-generation sequencing in routine diagnostics of non-syndromic IRD cases led to the discovery of pathogenic variants in JBTS genes that cause photoreceptor loss without other syndromic features. Here, we recapitulate these findings, describing the JBTS gene defects leading to non-syndromic IRDs.

Using in vivo cerebellar electroporation to study neuronal cell proliferation and differentiation in a Joubert syndrome mouse model.

Joubert syndrome (JS) is an autosomal recessive ciliopathy that mainly affects the morphogenesis of the cerebellum and brain stem. To date, mutations in at least 39 genes have been identified in JS; all these gene-encoding proteins are involved in the biogenesis of the primary cilium and centrioles. Recent studies using the mouse model carrying deleted or mutated JS-related genes exhibited cerebellar hypoplasia with a reduction in neurogenesis; however, investigating specific neuronal behaviors during their development in vivo remains challenging. Here, we describe an in vivo cerebellar electroporation technique that can be used to deliver plasmids carrying GFP and/or shRNAs into the major cerebellar cell type, granule neurons, from their progenitor state to their maturation in a spatiotemporal-specific manner. By combining this method with cerebellar immunostaining and EdU incorporation, these approaches enable the investigation of the cell-autonomous effect of JS-related genes in granule neuron progenitors, including the pathogenesis of ectopic neurons and the defects in neuronal differentiation. This approach provides information toward understanding the multifaceted roles of JS-related genes during cerebellar development in vivo.

RPI-1 (human DCDC2) displays functional redundancy with Nephronophthisis 4 in regulating cilia biogenesis in C. elegans.

Projecting from most cell surfaces, cilia serve as important hubs for sensory and signaling processes and have been linked to a variety of human disorders, including Bardet-Biedl Syndrome (BBS), Meckel-Gruber Syndrome (MKS), Nephronophthisis (NPHP), and Joubert Syndrome, and these diseases are collectively known as a ciliopathy. DCDC2 is a ciliopathy protein that localizes to cilia; nevertheless, our understanding of the role of DCDC2 in cilia is still limited. We employed C. elegans to investigate the function of C. elegans RPI-1, a Caenorhabditis elegans ortholog of human DCDC2, in cilia and found that C. elegans RPI-1 localizes to the entire ciliary axoneme, but is not present in the transition zone and basal body. We generated a null mutant of C. elegans rpi-1, and our analysis with a range of fluorescence-based ciliary markers revealed that DCDC2 and nephronophthisis 4 (NPHP-4/NPHP4) display functional redundant roles in regulating cilia length and cilia positions. Taken together, our analysis discovered a novel genetic interaction between two ciliopathy disease genes (RPI-1/DCDC2 and NPHP-4/NPHP4) in C. elegans.

Joubert Syndrome in 10-Year-Old with Renal Involvement: A Case Study

Joubert Syndrome in 10-Year-Old with Renal Involvement: A Case Study

Retinal Degeneration Animal Models in Bardet-Biedl Syndrome and Related Ciliopathies.

Retinal degeneration due to photoreceptor ciliary-related proteins dysfunction accounts for more than 25% of all inherited retinal dystrophies. The cilium, being an evolutionarily conserved and ubiquitous organelle implied in many cellular functions, can be investigated by way of many models from invertebrate models to nonhuman primates, all these models have massively contributed to the pathogenesis understanding of human ciliopathies. Taking the Bardet-Biedl syndrome (BBS) as an emblematic example as well as other related syndromic ciliopathies, the contribution of a wide range of models has enabled to characterize the role of the BBS proteins in the archetypical cilium but also at the level of the connecting cilium of the photoreceptors. There are more than 24 BBS genes encoding for proteins that form different complexes such as the BBSome and the chaperone proteins complex. But how they lead to retinal degeneration remains a matter of debate with the possible accumulation of proteins in the inner segment and/or accumulation of unwanted proteins in the outer segment that cannot return in the inner segment machinery. Many BBS proteins (but not the chaperonins for instance) can be modeled in primitive organisms such as Paramecium, Chlamydomonas reinardtii, Trypanosoma brucei, and Caenorhabditis elegans These models have enabled clarifying the role of a subset of BBS proteins in the primary cilium as well as their relations with other modules such as the intraflagellar transport (IFT) module, the nephronophthisis (NPHP) module, or the Meckel-Gruber syndrome (MKS)/Joubert syndrome (JBTS) module mostly involved with the transition zone of the primary cilia. Assessing the role of the primary cilia structure of the connecting cilium of the photoreceptor cells has been very much studied by way of zebrafish modeling (Danio rerio) as well as by a plethora of mouse models. More recently, large animal models have been described for three BBS genes and one nonhuman primate model in rhesus macaque for BBS7 In completion to animal models, human cell models can now be used notably thanks to gene editing and the use of induced pluripotent stem cells (iPSCs). All these models are not only important for pathogenesis understanding but also very useful for studying therapeutic avenues, their pros and cons, especially for gene replacement therapy as well as pharmacological triggers.

Cystic Diseases of the Kidneys: From Bench to Bedside.

Exploration into the causes of hereditary renal cystic diseases demonstrates a deep-rooted connection with the proteomic components of the cellular organelle cilia. Cilia are essential to the signaling cascades, and their dysfunction has been tied to a range of renal cystic diseases initiating with studies on the oak ridge polycystic kidney (ORPK) mouse model. Here, we delve into renal cystic pathologies that have been tied with ciliary proteosome and highlight the genetics associated with each. The pathologies are grouped based on the mode of inheritance, where inherited causes that result in cystic kidney disease phenotypes include autosomal dominant and autosomal recessive polycystic kidney disease, nephronophthisis (Bardet-Biedl syndrome and Joubert Syndrome), and autosomal dominant tubulointerstitial kidney disease. Alternatively, phakomatoses-, also known as neurocutaneous syndromes, associated cystic kidney diseases include tuberous sclerosis (TS) and Von Hippel-Lindau (VHL) disease. Additionally, we group the pathologies by the mode of inheritance to discuss variations in recommendations for genetic testing for biological relatives of a diagnosed individual.

Joubert Syndrome: Diagnostic Evaluation and Follow-up

AbstractThe follow-up of a child with genetic syndrome is necessarily multidisciplinary because of the multiplicity of problems and calls for close collaboration between different specialists. The primary objective is the total care of the child and his family, regardless of the rarity and complexity of the disease, to obtain the highest possible degree of mental and physical health and autonomy.

Compound heterozygous splicing variants in KIAA0586 cause fetal short-rib thoracic dysplasia and cerebellar malformation: Use of exome sequencing in prenatal diagnosis.

Short-rib thoracic dysplasia (SRTD) and Joubert syndrome (JS) are rare genetic ciliopathies, and individuals with either syndrome can manifest cerebellar malformation and variable developmental delays. However, neither of these conditions is easily diagnosed during pregnancy due to a limited fetal phenotype. Here, we investigated a fetus that was initially observed to have short limbs and polydactyly and discovered a compound heterozygous pathogenesis through exome sequencing (ES). Simultaneous trio-ES and chromosome microarray analysis was provided for the fetus. The presence and effects of these variants on splicing were further validated at the DNA and RNA levels. Only short limbs and post-axial polydactyly of the fetus were detected during the second trimester. Two variants (c.3940+1G>A and c.3303G>A), affecting splicing of KIAA0586, were identified from amniocytes through ES and validated by Sanger sequencing. More intensive fetal monitoring was applied, and the fetus was also found to have deformed cerebellar malformation and a constricted thoracic cage. Herein, we report the genetic pathogenesis of SRTD and/or JS associated with KIAA0586 in a fetus. The novel splicing variants observed expand the spectrum of KIAA0586 in SRTD and/or JS. Based on the genetic data and the distinct corresponding phenotypes discovered by imaging examination, a comprehensive diagnosis was made during pregnancy and more valuable prognostic information was provided for the parents.

Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome

ObjectiveJoubert syndrome is a neurodevelopmental disorder with a distinctive hindbrain malformation called molar tooth sign, causing motor and cognitive impairments. More than 40 genes have been associated with Joubert syndrome. We aim to describe a group of Joubert syndrome patients clinically and genetically emphasizing organ involvement. MethodsWe retrospectively collected clinical information and molecular diagnosis data of 22 patients with Joubert syndrome from multiple facilities. Clinical exome or whole-exome sequencing were performed to identify causal variations in genes. ResultsThe most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes. Multi-systemic organ involvement was observed in nine (40%) patients, with the eye being the most common, including Leber’s congenital amaurosis, ptosis, and optic nerve coloboma. Portal hypertension and esophageal varices as liver and polycystic kidney disease and nephronophthisis as kidney involvement was encountered in our patients. The HYLS1 gene, which commonly causes hydrolethalus syndrome 1, was also associated with Joubert syndrome in one of our patients. A mild phenotype with hypophyseal hormone deficiencies without the classical molar tooth sign was observed with compound heterozygous and likely pathogenic variants not reported before in the KATNIP gene. ConclusionSome rare variants that display prominent genetic heterogeneity with variable severity are first reported in our patients. In our study of 22 Joubert syndrome patients, CPLANE1 is the most affected gene, and Joubert syndrome as a ciliopathy is possible without a classical molar tooth sign, like in the KATNIP gene-affected patients.

Generation of an iPSC line from skin fibroblasts of a patient with Joubert syndrome carrying the homozygous loss of function variant c.787dupC in the AHI1 gene

We produced an iPSC line from a patient with Joubert syndrome carrying the homozygous c.787dupC variant in the AHI1 gene. The iPSC line was obtained by reprogramming skin fibroblasts, mycoplasma-free, using Sendai-virus-based technique. Characterization of iPSCs showed the same Short Tandem Repeats profile than fibroblasts, normal karyotype, expression of staminal markers (OCT4, SOX2, SSEA4 and NANOG) and ability to differentiate into three germ layers in vitro.