Joubert syndrome: congenital cerebellar ataxia with the molar tooth.
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Joubert syndrome is a congenital cerebellar ataxia with autosomal recessive or X-linked inheritance, the diagnostic hallmark of which is a unique Cerebellar and brainstem malformation recognisable on brain imaging-the so-called molar tooth sign.Abstract:
Summary Joubert syndrome is a congenital cerebellar ataxia with autosomal recessive or X-linked inheritance, the diagnostic hallmark of which is a unique cerebellar and brainstem malformation recognisable on brain imaging—the so-called molar tooth sign. Neurological signs are present from the neonatal period and include hypotonia progressing to ataxia, global developmental delay, ocular motor apraxia, and breathing dysregulation. These signs are variably associated with multiorgan involvement, mainly of the retina, kidneys, skeleton, and liver. 21 causative genes have been identified so far, all of which encode for proteins of the primary cilium or its apparatus. The primary cilium is a subcellular organelle that has key roles in development and in many cellular functions, making Joubert syndrome part of the expanding family of ciliopathies. Notable clinical and genetic overlap exists between distinct ciliopathies, which can co-occur even within families. Such variability is probably explained by an oligogenic model of inheritance, in which the interplay of mutations, rare variants, and polymorphisms at distinct loci modulate the expressivity of the ciliary phenotype.read more
Citations
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Motile and non-motile cilia in human pathology: from function to phenotypes.
TL;DR: The diverse functions of cilia in human health and disease are reviewed and a growing shift away from the classical clinical definitions of ciliopathy syndromes to a more functional categorization is discussed.
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Consensus Paper: Cerebellar Development.
Ketty Leto,Marife Arancillo,Esther B. E. Becker,Annalisa Buffo,Chin Chiang,Baojin Ding,William B. Dobyns,William B. Dobyns,Isabelle Dusart,Isabelle Dusart,Parthiv Haldipur,Mary E. Hatten,Mikio Hoshino,Alexandra L. Joyner,Masanobu Kano,Daniel L. Kilpatrick,Noriyuki Koibuchi,Silvia Marino,Salvador Martinez,Kathleen J. Millen,Thomas O Millner,Takaki Miyata,Elena Parmigiani,Karl Schilling,Gabriella Sekerková,Roy V. Sillitoe,Constantino Sotelo,Naofumi Uesaka,Annika K. Wefers,Richard J. T. Wingate,Richard Hawkes +30 more
TL;DR: The main processes of cerebellar ontogenesis are described, highlighting the neurogenic strategies used by developing progenitors, the genetic programs involved in cell fate specification, the progressive changes of structural organization, and some of the better-known abnormalities associated with developmental disorders of the cerebellum.
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Primary cilia in the developing and mature brain
TL;DR: Primary cilia are recognized as key integrators of extracellular ligand-based signaling and cellular polarity, which regulate neuronal cell fate, migration, differentiation, as well as a host of adult behaviors.
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Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity.
Ruxandra Bachmann-Gagescu,Jennifer C. Dempsey,Ian G. Phelps,Brian J. O'Roak,Dana M. Knutzen,Tessa Rue,Gisele E. Ishak,Christine R. Isabella,Nicholas T. Gorden,Jonathan Adkins,Evan A. Boyle,N. de Lacy,Diana R. O’Day,Abdulrahman Alswaid,Radha Ramadevi A,L Lingappa,Charles Marques Lourenço,Loreto Martorell,Angels García-Cazorla,Hamit Özyürek,G Haliloğlu,Beyhan Tüysüz,Meral Topçu,Phillip F. Chance,Melissa A. Parisi,I A Glass,Jay Shendure,Dan Doherty +27 more
TL;DR: This work illustrates how combining advanced sequencing techniques with phenotypic data addresses extreme genetic heterogeneity to provide diagnostic and carrier testing, guide medical monitoring for progressive complications, facilitate interpretation of genome-wide sequencing results in individuals with a variety of phenotypes and enable gene-specific treatments in the future.
Journal ArticleDOI
An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes
Gabrielle Wheway,Miriam Schmidts,Dorus A. Mans,Katarzyna Szymanska,Thanh Minh T. Nguyen,Hilary E. Racher,Ian G. Phelps,Grischa Toedt,Julie Kennedy,Kirsten A. Wunderlich,Nasrin Sorusch,Zakia Abdelhamed,Subaashini Natarajan,Warren Herridge,Jeroen van Reeuwijk,Nicola Horn,Karsten Boldt,David A. Parry,Stef J.F. Letteboer,Susanne Roosing,Matthew Adams,Sandra M. Bell,Jacquelyn Bond,Julie Higgins,Ewan E. Morrison,Darren C. Tomlinson,Gisela G. Slaats,Teunis J. P. van Dam,Lijia Huang,Kristin Kessler,Andreas Giessl,Clare V. Logan,Evan A. Boyle,Jay Shendure,Shamsa Anazi,Mohammed A. Aldahmesh,Selwa A. Al Hazzaa,Selwa A. Al Hazzaa,Robert A. Hegele,Carole Ober,Patrick Frosk,Aizeddin A. Mhanni,Bernard N. Chodirker,Albert E. Chudley,Ryan E. Lamont,Francois P. Bernier,Chandree L. Beaulieu,Paul M. K. Gordon,Richard T. Pon,Clem Donahue,A. James Barkovich,Louis Wolf,Carmel Toomes,Christian Thiel,Kym M. Boycott,Martin McKibbin,Chris F. Inglehearn,Fiona Stewart,Heymut Omran,Martijn A. Huynen,Panagiotis I. Sergouniotis,Panagiotis I. Sergouniotis,Fowzan S. Alkuraya,Jillian S. Parboosingh,A. Micheil Innes,Colin E. Willoughby,Rachel H. Giles,Andrew R. Webster,Andrew R. Webster,Marius Ueffing,Marius Ueffing,Oliver E. Blacque,Joseph G. Gleeson,Uwe Wolfrum,Philip L. Beales,Toby J. Gibson,Dan Doherty,Hannah M. Mitchison,Ronald Roepman,Colin A. Johnson +79 more
TL;DR: A whole-genome siRNA-based reverse genetics screen for defects in biogenesis and/or maintenance of the primary cilium is described and insights into ciliogenesis complexity and roles for unanticipated pathways in human genetic disease are provided.
References
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Journal ArticleDOI
The primary cilium: a signalling centre during vertebrate development
TL;DR: The connections between cilia and developmental signalling have begun to clarify the basis of human diseases associated with ciliary dysfunction, and the cilium represents a nexus for signalling pathways during development.
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Triallelic Inheritance in Bardet-Biedl Syndrome, a Mendelian Recessive Disorder
Nicholas Katsanis,Stephen J. Ansley,Jose L. Badano,Erica R. Eichers,Richard A. Lewis,Bethan E. Hoskins,Peter J. Scambler,William S. Davidson,Philip L. Beales,James R. Lupski +9 more
TL;DR: In this paper, a cohort of 163 BBS families were screened for mutations in BBS2 and BBS6 and reported the presence of three mutant alleles in affected individuals in four pedigrees.
Journal ArticleDOI
A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition
Francesc R. Garcia-Gonzalo,Kevin C. Corbit,María Salomé Sirerol-Piquer,Gokul Ramaswami,Edgar A. Otto,Thomas R. Noriega,Allen D. Seol,Jon F. Robinson,Christopher L. Bennett,Dragana Josifova,José Manuel García-Verdugo,Nicholas Katsanis,Friedhelm Hildebrandt,Friedhelm Hildebrandt,Jeremy F. Reiter +14 more
TL;DR: A transition zone complex of Meckel and Joubert syndrome proteins regulates ciliary assembly and trafficking, suggesting that transition zone dysfunction is the cause of these ciliopathies.
Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder.
Nicholas Katsanis,Stephen J. Ansley,Jose L. Badano,Erica R. Eichers,Richard A. Lewis,Bethan E. Hoskins,Peter J. Scambler,William S. Davidson,Philip L. Beales,Lupski +9 more
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