Usher syndrome type 1–associated cadherins shape the photoreceptor outer segment

Schietroma, Cataldo; Parain, Karine; Estivalet, Amrit; Aghaie, Asadollah; Monvel, Jacques Boutet de; Picaud, Serge; Sahel, José‐Alain; Perron, Muriel; El-Amraoui, Aziz; Petit, Christine

doi:10.1083/jcb.201612030

Cited by 55 publications

(92 citation statements)

References 78 publications

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“…The Usher complex has been principally characterized in the inner ear where it forms 'tip-links' that connect adjacent stereocilia on the surface of mechanosensory hair cells (7). More recently, it has been proposed that the Usher complex also plays a role in organizing the actin-based microvilli-like calyceal processes that span the inner and outer segments of photoreceptor cells (8,9). Genetic disruption of components of the Usher complex results in Type 1 Usher Syndrome (USH1), a form of severe deafness-blindness in humans (10-16).…”

Section: Introductionmentioning

confidence: 99%

The small EF-hand protein CALML4 functions as a critical myosin light chain within the intermicrovillar adhesion complex

Choi

Graves

Matoo

et al. 2020

Journal of Biological Chemistry

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Specialized transporting and sensory epithelial cells employ homologous protocadherin-based adhesion complexes to remodel their apical membrane protrusions into organized functional arrays. Within the intestine, the nutrient-transporting enterocytes utilize the intermicrovillar adhesion complex (IMAC) to assemble their apical microvilli into an ordered brush border. The IMAC bears remarkable homology to the Usher complex, whose disruption results in the sensory disorder type 1 Usher syndrome (USH1). However, the entire complement of proteins that comprise both the IMAC and Usher complex are not yet fully elucidated. Using a protein isolation strategy to recover the IMAC, we have identified the small EF-hand protein calmodulin-like protein 4 (CALML4) as an IMAC component. Consistent with this finding, we show that CALML4 exhibits marked enrichment at the distal tips of enterocyte microvilli, the site of IMAC function, and is a direct binding partner of the IMAC component myosin-7b. Moreover, distal tip enrichment of CALML4 is strictly dependent upon its association with myosin-7b, with CALML4 acting as a light chain for this myosin. We further show that genetic disruption of CALML4 within enterocytes results in brush border assembly defects that mirror the loss of other IMAC components and that CALML4 can also associate with the Usher complex component myosin-7a. Our study further defines the molecular composition and protein-protein interaction network of the IMAC and Usher complex and may also shed light on the etiology of the sensory disorder USH1H.

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Section: Introductionmentioning

confidence: 99%

The small EF-hand protein CALML4 functions as a critical myosin light chain within the intermicrovillar adhesion complex

Choi

Graves

Matoo

et al. 2020

Journal of Biological Chemistry

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“…It has been reported that CDH23 is expressed in the stereocilia of the hair cells of the inner ear at the region of the connecting cilia at the junction between the inner and outer segments [13]. Besides, CDH23 is also harbored in the retina [14] within the calyceal processes of the cone photoreceptors [15]. CDH23 contains 70 exons that encode for approximately 3354 amino acids and has a cDNA size of 10 kb (https://www.uniprot.org/uniprot/Q9H251).…”

Section: Discussionmentioning

confidence: 99%

Molecular etiology of hereditary deafness using next generation sequencing in northwest China

Wang¹,

Li²,

Ding³

et al. 2020

Preprint

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Objective: To analyze the molecular etiology of 92 hereditary deafness families and explore the genetic mechanism of newly identified genes in deafness heritability. Methods: We analyzed the medical history, audiology, imaging, and physical examination data of 92 probands and their family members. Probands were selected from the hereditary deafness database; they did not have any of the common genetic mutation sites. Genomic DNA was extracted from blood samples and next generation sequencing was performed on an Illumina platform, followed by co-segregation analysis of family members. The control group included the clinical data and blood samples from 207 normal hearing people. Results: Among the 92 samples, 30 homozygous variants were identified in 29 autosomal recessive hereditary deafness families, including 6 reported mutations and 26 novel mutations. Among them, MYO15A was the most frequently detected (6/92), followed by mutations in CDH23, OTOF, FGF3 (3/92 each), MYO7A, SLC26A4, MYO6 (2/92 each), BSND, CLDN14, DFNB59, ILDR1, LHFPL5, LRTOMT, TMPRSS3, TPRN, USH1C, and LOXHD1 (1/92 each). Conclusion: In patients with autosomal recessive deafness, the MYO15A, CDH23, OTOF, and FGF3 genes could be used as candidate genes for conventional genetic studies in northwest China.

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“…fröschen, in denen Protocadherin 15 und Cadherin 23 herunterreguliert wurden, zeigen, dass beide USH-Cadherine für die Ausbildung der "calyceal processes" notwendig sind und ihr Fehlen zu Defekten in der Ausbildung und im Erhalt der Photorezeptoraußensegmente führt [49]. Weiterführende Erkenntnisse zur Funktion des USH-Netzwerkes in den "calyceal processes" sind von Nichtrodenten-USH-Säugermodellen, wie bspw.…”

Section: Funktion Der Ush-proteinnetzwerke In Haarsinneszellenunclassified

Das Usher-Syndrom, eine Ziliopathie des Menschen

Wolfrum

Nagel-Wolfrum

2018

Klin Monatsbl Augenheilkd

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The human Usher syndrome (USH) is a complex, rare disease manifesting in its most common form of inherited deaf-blindness. Due to the heterogeneous manifestation of the clinical symptoms, three clinical types (USH1-3) are distinguished according to the severity of the disease pattern. For a correct diagnosis, in addition to the auditory tests in early newborn screening, ophthalmological examinations and molecular genetic analysis are important. Ten known USH genes encode proteins, which are from heterogeneous protein families, interact in functional protein networks. In the eye and in the ear, USH proteins are expressed primarily in the mechano-sensitive hair cells and the rod and cone photoreceptor cells, respectively. In the hair cells, the USH protein networks are essential for the correct differentiation of the hair bundles as well as for the function of the mechano-electrical transduction complex in the matured cell. In the photoreceptor cells, USH proteins are located in the ciliary region and participate in intracellular transport processes. In addition, a USH protein network is present in the so-called calyceal processes. The lack of calyceal processes and the absence of a prominent visual phenotype in the mouse disqualifies mice as models for studies on the ophthalmic component of USH. While hearing impairments can be compensated with hearing aids and cochlear implants, there is no practical therapy for USH in the eye. Currently, gene-based therapy concepts, such as gene addition, applications of antisense oligonucleotides and TRIDs ("translational readthrough inducing drugs") for the readthrough of nonsense mutations are preclinically evaluated. For USH1B/MYO7A the UshStat gene therapy clinical trial is ongoing.

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Usher syndrome type 1–associated cadherins shape the photoreceptor outer segment

Cited by 55 publications

References 78 publications

The small EF-hand protein CALML4 functions as a critical myosin light chain within the intermicrovillar adhesion complex

The small EF-hand protein CALML4 functions as a critical myosin light chain within the intermicrovillar adhesion complex

Molecular etiology of hereditary deafness using next generation sequencing in northwest China

Das Usher-Syndrom, eine Ziliopathie des Menschen

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