0000000000520505
AUTHOR
Nicholas Katsanis
showing 8 related works from this author
Association of Whirlin with Cav1.3 (α1D) Channels in Photoreceptors, Defining a Novel Member of the Usher Protein Network
2010
Contains fulltext : 88383.pdf (Publisher’s version ) (Closed access) PURPOSE: Usher syndrome is the most common form of hereditary deaf-blindness. It is both clinically and genetically heterogeneous. The USH2D protein whirlin interacts via its PDZ domains with other Usher-associated proteins containing a C-terminal type I PDZ-binding motif. These proteins co-localize with whirlin at the region of the connecting cilium and at the synapse of photoreceptor cells. This study was undertaken to identify novel, Usher syndrome-associated, interacting partners of whirlin and thereby obtain more insights into the function of whirlin. METHODS: The database of ciliary proteins was searched for proteins…
A Transition Zone Complex Regulates Mammalian Ciliogenesis and Ciliary Membrane Composition
2011
Mutations in genes encoding ciliary components cause ciliopathies, but how many of these mutations disrupt ciliary function is unclear. We investigated Tectonic1 (Tctn1), a regulator of mouse Hedgehog signaling, and found that it is essential for ciliogenesis in some, but not all, tissues. Cell types that do not require Tctn1 for ciliogenesis require it to localize select membrane-associated proteins to the cilium, including Arl13b, AC3, Smoothened and Pkd2. Tctn1 forms a complex with multiple ciliopathy proteins associated with Meckel (MKS) and Joubert (JBTS) syndromes, including Mks1, Tmem216, Tmem67, Cep290, B9d1, Tctn2, and Cc2d2a. Components of the Tectonic ciliopathy complex colocaliz…
SYSCILIA, “A systems biology approach to dissect cilia function and its disruption in human genetic disease”
2012
Primary cilia are basically signaling hubs, harboring amongst others the noncanonical WNT, Hedgehog,and PDGF signaling systems, and their disruption leads to striking developmental defects. Some ciliopathy-associated proteins have recently been revealed to be physically or functionally associated in several distinct groupings, with limited connections to other crucial biological processes. Early proteomics studies have also suggested a discrete repertoire of about 1000 proteins within the organelle (i.e. <5% of the proteome) that are still in need of organisation into pathways and networks. Small, relatively isolated systems are often targeted by systems biology approaches under the assumpt…
Mutations in ATP13A2 (PARK9) are associated with an amyotrophic lateral sclerosis-like phenotype, implicating this locus in further phenotypic expans…
2019
Background Amyotrophic lateral sclerosis [1] is a genetically heterogeneous neurodegenerative disorder, characterized by late-onset degeneration of motor neurons leading to progressive limb and bulbar weakness, as well as of the respiratory muscles, which is the primary cause of disease fatality. To date, over 25 genes have been implicated as causative in ALS with C9orf72, SOD1, FUS, and TARDBP accounting for the majority of genetically positive cases. Results We identified two patients of Italian and French ancestry with a clinical diagnosis of juvenile-onset ALS who were mutation-negative in any of the known ALS causative genes. Starting with the index case, a consanguineous family of Ita…
Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility
2018
International audience; Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing, and bone fragility. Whole-exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A) as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss-of-function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut dev…
Osteo-Oto-Hepato-Enteric Syndrome (O2HE) is caused by loss of function mutations in UNC45A
2017
AbstractDespite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with hitherto unknown syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing and bone fragility, a clinical entity we have termed O2HE (Osteo-Oto-Hepato-enteric) syndrome. Whole exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A), as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss of function paradigm, wherein mutations …
An organelle-specific protein landscape identifies novel diseases and molecular mechanisms.
2016
Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub…
Additional file 1: of Mutations in ATP13A2 (PARK9) are associated with an amyotrophic lateral sclerosis-like phenotype, implicating this locus in fur…
2019
Figure S1. a Schematic of the endogenous zebrafish atp13a2 ortholog. The exons are shown are rectangles and the introns as horizontal lines. The splice junctions targeted with antisense morpholino oligonucleotides (atp13a2_3x4_SB and atp13a2_3x6_SB) are shown with red asterisks. b Gel images showing the efficiency of the atp13a2_3x4_SB and atp13a2_3x6_SB morpholinos. The first lane in each gel photograph shows amplicons from the respective loci flanking the targeted sequences, with no aberrations observed. In the embryos injected with morpholino oligonucleotides, aberrant bands were evident, showing that the morpholinos were efficient in knocking down the expression of endogenous atp13a2. F…