Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility

Estève, Clothilde; Francescatto, Ludmila; Tan, Perciliz L.; Bourchany, Aurélie; Leusse, Cécile de; Marinier, Evelyne; Blanchard, Arnaud; Bourgeois, P.; Brochier-Armanet, Céline; Bruel, Ange‐Line; Delarue, A.; Duffourd, Yannis; Ecochard-Dugelay, Emmanuelle; Hery, G.; Huet, Frédéric; Gauchez, Philippe; Gonzalès, Emmanuel; Guettier-Bouttier, Catherine; Komuta, Mina; Lacoste, Caroline; Maudinas, R.; Mazodier, K.; Rimet, Y.; Rivière, Jean‐Baptiste; Roquelaure, Bertrand; Sigaudy, Sabine; Stéphenne, Xavier; Thauvin‐Robinet, Christel; Thévenon, Julien; Sarles, J.; Lévy, Nicolas; Badens, Catherine; Goulet, Olivier; Hugot, Jean‐Pierre; Katsanis, Nicholas; Faivre, Laurence; Fabre, Alexandre

doi:10.1016/j.ajhg.2018.01.009

Cited by 45 publications

(51 citation statements)

References 34 publications

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“…Cochlear hair cells express both UNC45A and UNC45B ( https://umgear.org ), and we hypothesize that either one of these chaperones is required for the correct folding of MYO15 in vivo . Intriguingly, loss-of-function mutations in UNC45A are associated with a human form of syndromic deafness ( 56 ), although it is unknown whether this is caused by defective hair cell stereocilia formation, similar to the phenotype caused by pathogenic Myo15 variants in mouse ( 3 , 5 ). Why might hair cells express both UNC45 paralogs?…”

Section: Discussionmentioning

confidence: 99%

The ATPase mechanism of myosin 15, the molecular motor mutated in DFNB3 human deafness

Jiang

Takagi

Shams

et al. 2021

Journal of Biological Chemistry

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Cochlear hair cells each possess an exquisite bundle of actin-based stereocilia that detect sound. Unconventional myosin 15 (MYO15) traffics and delivers critical molecules required for stereocilia development and thus is essential for building the mechanosensory hair bundle. Mutations in the human MYO15A gene interfere with stereocilia trafficking and cause hereditary hearing loss, DFNB3, but the impact of these mutations is not known, as MYO15 itself is poorly characterized. To learn more, we performed a kinetic study of the ATPase motor domain to characterize its mechanochemical cycle. Using the baculovirus– Sf 9 system, we purified a recombinant minimal motor domain (S1) by coexpressing the mouse MYO15 ATPase, essential and regulatory light chains that bind its IQ domains, and UNC45 and HSP90A chaperones required for correct folding of the ATPase. MYO15 purified with either UNC45A or UNC45B coexpression had similar ATPase activities ( k cat = ∼ 6 s −1 at 20 °C). Using stopped-flow and quenched-flow transient kinetic analyses, we measured the major rate constants describing the ATPase cycle, including ATP, ADP, and actin binding; hydrolysis; and phosphate release. Actin-attached ADP release was the slowest measured transition (∼12 s −1 at 20 °C), although this did not rate-limit the ATPase cycle. The kinetic analysis shows the MYO15 motor domain has a moderate duty ratio (∼0.5) and weak thermodynamic coupling between ADP and actin binding. These findings are consistent with MYO15 being kinetically adapted for processive motility when oligomerized. Our kinetic characterization enables future studies into how deafness-causing mutations affect MYO15 and disrupt stereocilia trafficking necessary for hearing.

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Section: Discussionmentioning

confidence: 99%

The ATPase mechanism of myosin 15, the molecular motor mutated in DFNB3 human deafness

Jiang

Takagi

Shams

et al. 2021

Journal of Biological Chemistry

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“…This protein contributes to tumorigenesis by regulating cancer cell proliferation [ 38 ]. In addition, biallelic loss-of-function mutations in this gene cause the development of osteo-oto-hepato-enteric syndrome, which includes the clinical features of cholestasis, congenital diarrhea, impaired hearing, and bone fragility [ 39 ]. Therefore, the protein encoded by UNC45A may have important physiological functions in several organ systems.…”

Section: Discussionmentioning

confidence: 99%

Controlled human exposures to diesel exhaust: a human epigenome-wide experiment of target bronchial epithelial cells

Fadadu

Laan

Ward‐Caviness

et al. 2021

Environmental Epigenetics

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Diesel exhaust (DE) is a major contributor to ambient air pollution around the world. It is a known human carcinogen that targets the respiratory system and increases risk for many diseases, but there is limited research on the effects of DE exposure on the epigenome of human bronchial epithelial cells. Understanding the epigenetic impact of this environmental pollutant can elucidate biological mechanisms involved in the pathogenesis of harmful DE-related health effects. To estimate the causal effect of short-term DE exposure on the bronchial epithelial epigenome, we conducted a controlled single-blinded randomized crossover human experiment of exposure to DE and used bronchoscopy and Illumina 450K arrays for data collection and analysis, respectively. Of the 13 participants, 11 (85%) were male and 2 (15%) were female, and 12 (92%) were White and one (8%) was Hispanic; the mean age was 26 years (SD = 3.8 years). Eighty CpGs were differentially methylated, achieving the minimum possible exact P-value of P = 2.44 × 10−4 (i.e. 2/213). In regional analyses, we found two differentially methylated regions (DMRs) annotated to the chromosome 5 open reading frame 63 genes (C5orf63; 7-CpGs) and unc-45 myosin chaperone A gene (UNC45A; 5-CpGs). Both DMRs showed increased DNA methylation after DE exposure. The average causal effects for the DMRs ranged from 1.5% to 6.0% increases in DNA methylation at individual CpGs. In conclusion, we found that short-term DE alters DNA methylation of genes in target bronchial epithelial cells, demonstrating epigenetic level effects of exposure that could be implicated in pulmonary pathologies.

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“…Lastly, we found that UNC-45A is abundantly expressed in both the ciliated columnar epithelium of the fallopian tube and the cilia of the ependymocytes. Interestingly, congenital loss-of-function mutations in UNC-45A cause a syndrome characterized by diarrhea, cholestasis, bone fragility, and impaired hearing [ 56 ], all of which symptoms involve organs where cilia play important roles in physiology [ 57 , 58 , 59 ]. Furthermore, almost all of the subjects affected by congenital UNC-45A loss have signs of intellectual disability [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, congenital loss-of-function mutations in UNC-45A cause a syndrome characterized by diarrhea, cholestasis, bone fragility, and impaired hearing [ 56 ], all of which symptoms involve organs where cilia play important roles in physiology [ 57 , 58 , 59 ]. Furthermore, almost all of the subjects affected by congenital UNC-45A loss have signs of intellectual disability [ 56 ]. Although this may be partially due to deafness or/and other aspecific and indirect causes associated with the syndrome, it is also possible that UNC-45A loss may be directly responsible for the intellectual disability of these patients given its wide expression in the central nervous system and its requirement for the extension of neurites [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

UNC-45A Is Highly Expressed in the Proliferative Cells of the Mouse Genital Tract and in the Microtubule-Rich Areas of the Mouse Nervous System

Clemente

Hoshino

Meints

et al. 2021

Cells

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UNC-45A (Protein unc-45 homolog A) is a cytoskeletal-associated protein with a dual and non-mutually exclusive role as a regulator of the actomyosin system and a Microtubule (MT)-destabilizing protein, which is overexpressed in human cancers including in ovarian cancer patients resistant to the MT-stabilizing drug paclitaxel. Mapping of UNC-45A in the mouse upper genital tract and central nervous system reveals its enrichment not only in highly proliferating and prone to remodeling cells, but also in microtubule-rich areas, of the ovaries and the nervous system, respectively. In both apparatuses, UNC-45A is also abundantly expressed in the ciliated epithelium. As regulators of actomyosin contractility and MT stability are essential for the physiopathology of the female reproductive tract and of neuronal development, our findings suggest that UNC-45A may have a role in ovarian cancer initiation and development as well as in neurodegeneration.

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Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility

Cited by 45 publications

References 34 publications

The ATPase mechanism of myosin 15, the molecular motor mutated in DFNB3 human deafness

The ATPase mechanism of myosin 15, the molecular motor mutated in DFNB3 human deafness

Controlled human exposures to diesel exhaust: a human epigenome-wide experiment of target bronchial epithelial cells

UNC-45A Is Highly Expressed in the Proliferative Cells of the Mouse Genital Tract and in the Microtubule-Rich Areas of the Mouse Nervous System

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