@article {538, title = {Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies.}, journal = {Hum Mutat}, volume = {39}, year = {2018}, month = {2018 01}, pages = {152-166}, abstract = {

Defects in the biosynthesis and/or function of primary cilia cause a spectrum of disorders collectively referred to as ciliopathies. A subset of these disorders is distinguished by profound abnormalities of the skeleton that include a long narrow chest with markedly short ribs, extremely short limbs, and polydactyly. These include the perinatal lethal short-rib polydactyly syndromes (SRPS) and the less severe asphyxiating thoracic dystrophy (ATD), Ellis-van Creveld (EVC) syndrome, and cranioectodermal dysplasia (CED) phenotypes. To identify new genes and define the spectrum of mutations in the skeletal ciliopathies, we analyzed 152 unrelated families with SRPS, ATD, and EVC. Causal variants were discovered in 14 genes in 120 families, including one newly associated gene and two genes previously associated with other ciliopathies. These three genes encode components of three different ciliary complexes; FUZ, which encodes a planar cell polarity complex molecule; TRAF3IP1, which encodes an anterograde ciliary transport protein; and LBR, which encodes a nuclear membrane protein with sterol reductase activity. The results established the molecular basis of SRPS type IV, in which mutations were identified in four different ciliary genes. The data provide systematic insight regarding the genotypes associated with a large cohort of these genetically heterogeneous phenotypes and identified new ciliary components required for normal skeletal development.

}, keywords = {Ciliopathies, Cytoplasmic Dyneins, Genetic Association Studies, Genetic Markers, Genetic Variation, Genotype, Humans, Mutation, Phenotype, Proteins, Radiography, Skeleton, Whole Exome Sequencing}, issn = {1098-1004}, doi = {10.1002/humu.23362}, author = {Zhang, Wenjuan and Taylor, S Paige and Ennis, Hayley A and Forlenza, Kimberly N and Duran, Ivan and Li, Bing and Sanchez, Jorge A Ortiz and Nevarez, Lisette and Nickerson, Deborah A and Bamshad, Michael and Lachman, Ralph S and Krakow, Deborah and Cohn, Daniel H} } @article {392, title = {Mutations in ARMC9, which Encodes a Basal Body Protein, Cause Joubert Syndrome in Humans and Ciliopathy Phenotypes in Zebrafish.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Jul 06}, pages = {23-36}, abstract = {

Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by hypotonia, ataxia, abnormal eye movements, and variable cognitive impairment. It is defined by a distinctive brain malformation known as the "molar tooth sign" on axial MRI. Subsets of affected individuals have malformations such as coloboma, polydactyly, and encephalocele, as well as progressive retinal dystrophy, fibrocystic kidney disease, and liver fibrosis. More than 35 genes have been associated with JS, but in a subset of families the genetic cause remains unknown. All of the gene products localize in and around the primary cilium, making JS a canonical ciliopathy. Ciliopathies are unified by their overlapping clinical features and underlying mechanisms involving ciliary dysfunction. In this work, we identify biallelic rare, predicted-deleterious ARMC9 variants (stop-gain, missense, splice-site, and single-exon deletion) in 11 individuals with JS from 8 families, accounting for approximately 1\% of the disorder. The associated phenotypes range from isolated neurological involvement to JS with retinal dystrophy, additional brain abnormalities (e.g., heterotopia, Dandy-Walker malformation), pituitary insufficiency, and/or synpolydactyly. We show that ARMC9 localizes to the basal body of the cilium and is upregulated during ciliogenesis. Typical ciliopathy phenotypes (curved body shape, retinal dystrophy, coloboma, and decreased cilia) in a CRISPR/Cas9-engineered zebrafish mutant model provide additional support for ARMC9 as a ciliopathy-associated gene. Identifying ARMC9 mutations as a cause of JS takes us one step closer to a full genetic understanding of this important disorder and enables future functional work to define the central biological mechanisms underlying JS and other ciliopathies.

}, keywords = {Abnormalities, Multiple, Animals, Armadillo Domain Proteins, Basal Bodies, Base Sequence, Brain, Cerebellum, Cilia, Ciliopathies, Diagnostic Imaging, Exome, Eye Abnormalities, Genetic Predisposition to Disease, Humans, Kidney Diseases, Cystic, Mutation, Phenotype, Retina, Sequence Analysis, DNA, Up-Regulation, Zebrafish, Zebrafish Proteins}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.05.010}, author = {Van De Weghe, Julie C and Rusterholz, Tamara D S and Latour, Brooke and Grout, Megan E and Aldinger, Kimberly A and Shaheen, Ranad and Dempsey, Jennifer C and Maddirevula, Sateesh and Cheng, Yong-Han H and Phelps, Ian G and Gesemann, Matthias and Goel, Himanshu and Birk, Ohad S and Alanzi, Talal and Rawashdeh, Rifaat and Khan, Arif O and Bamshad, Michael J and Nickerson, Deborah A and Neuhauss, Stephan C F and Dobyns, William B and Alkuraya, Fowzan S and Roepman, Ronald and Bachmann-Gagescu, Ruxandra and Doherty, Dan} } @article {60, title = {The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery.}, journal = {Nat Genet}, volume = {48}, year = {2016}, month = {2016 06}, pages = {648-56}, abstract = {

Cilia use microtubule-based intraflagellar transport (IFT) to organize intercellular signaling. Ciliopathies are a spectrum of human diseases resulting from defects in cilia structure or function. The mechanisms regulating the assembly of ciliary multiprotein complexes and the transport of these complexes to the base of cilia remain largely unknown. Combining proteomics, in vivo imaging and genetic analysis of proteins linked to planar cell polarity (Inturned, Fuzzy and Wdpcp), we identified and characterized a new genetic module, which we term CPLANE (ciliogenesis and planar polarity effector), and an extensive associated protein network. CPLANE proteins physically and functionally interact with the poorly understood ciliopathy-associated protein Jbts17 at basal bodies, where they act to recruit a specific subset of IFT-A proteins. In the absence of CPLANE, defective IFT-A particles enter the axoneme and IFT-B trafficking is severely perturbed. Accordingly, mutation of CPLANE genes elicits specific ciliopathy phenotypes in mouse models and is associated with ciliopathies in human patients.

}, keywords = {Animals, Ciliopathies, Flagella, Humans, Mice, Mutation, Phenotype, Protein Binding, Protein Transport, Proteins}, issn = {1546-1718}, doi = {10.1038/ng.3558}, author = {Toriyama, Michinori and Lee, Chanjae and Taylor, S Paige and Duran, Ivan and Cohn, Daniel H and Bruel, Ange-Line and Tabler, Jacqueline M and Drew, Kevin and Kelly, Marcus R and Kim, Sukyoung and Park, Tae Joo and Braun, Daniela A and Pierquin, Ghislaine and Biver, Armand and Wagner, Kerstin and Malfroot, Anne and Panigrahi, Inusha and Franco, Brunella and Al-Lami, Hadeel Adel and Yeung, Yvonne and Choi, Yeon Ja and Duffourd, Yannis and Faivre, Laurence and Rivi{\`e}re, Jean-Baptiste and Chen, Jiang and Liu, Karen J and Marcotte, Edward M and Hildebrandt, Friedhelm and Thauvin-Robinet, Christel and Krakow, Deborah and Jackson, Peter K and Wallingford, John B} } @article {35, title = {IFT52 mutations destabilize anterograde complex assembly, disrupt ciliogenesis and result in short rib polydactyly syndrome.}, journal = {Hum Mol Genet}, volume = {25}, year = {2016}, month = {2016 Sep 15}, pages = {4012-4020}, abstract = {

The short-rib polydactyly syndromes (SRPS) encompass a radiographically and genetically heterogeneous group of skeletal ciliopathies that are characterized by a long narrow chest, short extremities, and variable occurrence of polydactyly. Radiographic abnormalities include undermineralization of the calvarium, shortened and bowed appendicular bones, trident shaped acetabula and polydactyly. In a case of SRPS we identified compound heterozygosity for mutations in IFT52, which encodes a component of the anterograde intraflagellar transport complex. The IFT52 mutant cells synthesized a significantly reduced amount of IFT52 protein, leading to reduced synthesis of IFT74, IFT81, IFT88 and ARL13B, other key anterograde complex members. Ciliogenesis was also disrupted in the mutant cells, with a 60\% reduction in the presence of cilia on mutant cells and loss of cilia length regulation for the cells with cilia. These data demonstrate that IFT52 is essential for anterograde complex integrity and for the biosynthesis and maintenance of cilia. The data identify a new locus for SRPS and show that IFT52 mutations result in a ciliopathy with primary effects on the skeleton.

}, keywords = {Carrier Proteins, Cilia, Ciliopathies, Cytoskeletal Proteins, Flagella, Humans, Intracellular Signaling Peptides and Proteins, Multiprotein Complexes, Muscle Proteins, Mutation, Short Rib-Polydactyly Syndrome, Skeleton, Tumor Suppressor Proteins}, issn = {1460-2083}, doi = {10.1093/hmg/ddw241}, author = {Zhang, Wenjuan and Taylor, S Paige and Nevarez, Lisette and Lachman, Ralph S and Nickerson, Deborah A and Bamshad, Michael and Krakow, Deborah and Cohn, Daniel H} } @article {55, title = {Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes.}, journal = {J Med Genet}, volume = {53}, year = {2016}, month = {2016 09}, pages = {608-15}, abstract = {

BACKGROUND: Ciliopathies are an extensive group of autosomal recessive or X-linked disorders with considerable genetic and clinical overlap, which collectively share multiple organ involvement and may result in lethal or viable phenotypes. In large numbers of cases the genetic defect remains yet to be determined. The aim of this study is to describe the mutational frequency and phenotypic spectrum of the CEP120 gene.

METHODS: Exome sequencing was performed in 145 patients with Joubert syndrome (JS), including 15 children with oral-facial-digital syndrome type VI (OFDVI) and 21 Meckel syndrome (MKS) fetuses. Moreover, exome sequencing was performed in one fetus with tectocerebellar dysraphia with occipital encephalocele (TCDOE), molar tooth sign and additional skeletal abnormalities. As a parallel study, 346 probands with a phenotype consistent with JS or related ciliopathies underwent next-generation sequencing-based targeted sequencing of 120 previously described and candidate ciliopathy genes.

RESULTS: We present six probands carrying nine distinct mutations (of which eight are novel) in the CEP120 gene, previously found mutated only in Jeune asphyxiating thoracic dystrophy (JATD). The CEP120-associated phenotype ranges from mild classical JS in four patients to more severe conditions in two fetuses, with overlapping features of distinct ciliopathies that include TCDOE, MKS, JATD and OFD syndromes. No obvious correlation is evident between the type or location of identified mutations and the ciliopathy phenotype.

CONCLUSION: Our findings broaden the spectrum of phenotypes caused by CEP120 mutations that account for nearly 1\% of patients with JS as well as for more complex ciliopathy phenotypes. The lack of clear genotype-phenotype correlation highlights the relevance of comprehensive genetic analyses in the diagnostics of ciliopathies.

}, keywords = {Abnormalities, Multiple, Amino Acid Sequence, Cell Cycle Proteins, Cerebellar Diseases, Cerebellum, Child, Ciliopathies, Encephalocele, Eye Abnormalities, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Testing, Humans, Kidney Diseases, Cystic, Male, Mutation, Mutation Rate, Orofaciodigital Syndromes, Pedigree, Phenotype, Retina, Sequence Alignment}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2016-103832}, author = {Roosing, Susanne and Romani, Marta and Isrie, Mala and Rosti, Rasim Ozgur and Micalizzi, Alessia and Musaev, Damir and Mazza, Tommaso and Al-Gazali, Lihadh and Altunoglu, Umut and Boltshauser, Eugen and D{\textquoteright}Arrigo, Stefano and De Keersmaecker, Bart and Kayserili, H{\"u}lya and Brandenberger, Sarah and Kraoua, Ichraf and Mark, Paul R and McKanna, Trudy and Van Keirsbilck, Joachim and Moerman, Philippe and Poretti, Andrea and Puri, Ratna and Van Esch, Hilde and Gleeson, Joseph G and Valente, Enza Maria} }