De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome

Yuan, Yongyi; Zhang, Shiping; Chang, Qing; Zeng, Jin; Xin, Feng; Wang, Jianjun; Zhu, Qingyan; Wu, Jing; Lu, Jingqiao; Guo, Weiwei; Yan, Xukun; Jiang, Hui; Zhou, Baohua; Li, Qi; Gao, Xue; Yuan, Huijun; Yang, Shiming; Han, Dongyi; Mao, Zixu; Chen, Ping; Lin, Xiaobo; Dai, Pu

doi:10.1038/cr.2014.77

Cited by 59 publications

(78 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Besides sharing features of deafness (reversible via cochlear implant) and digital abnormalities, the latter syndrome causes intellectual disability. These familial mutations in V1B2 reduce v-ATPase function and impair lysosomal acidification (Yuan et al, 2014). …”

Section: V-atpase –Related Lysosomal Acidification Failure In Diseasementioning

confidence: 99%

Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease

Colacurcio

Nixon

2016

Ageing Research Reviews

401

329

View full text Add to dashboard Cite

Autophagy and endocytosis deliver unneeded cellular materials to lysosomes for degradation. Beyond processing cellular waste, lysosomes release metabolites and ions that serve signaling and nutrient sensing roles, linking the functions of the lysosome to various pathways for intracellular metabolism and nutrient homeostasis. Each of these lysosomal behaviors is influenced by the intraluminal pH of the lysosome, which is maintained in the low acidic range by a proton pump, the vacuolar ATPase (v-ATPase). New reports implicate altered v-ATPase activity and lysosomal pH dysregulation in cellular aging, longevity, and adult-onset neurodegenerative diseases, including forms of Parkinson Disease and Alzheimer Disease. Genetic defects of subunits composing the v-ATPase or v-ATPase-related proteins occur in an increasingly recognized group of familial neurodegenerative diseases. Here, we review the expanding roles of the v-ATPase complex as a platform regulating lysosomal proteolysis and cellular homeostasis. We discuss the unique vulnerability of neurons to persistent low level lysosomal dysfunction and review recent clinical and experimental studies that link dysfunction of the v-ATPase complex to neurodegenerative diseases across the age spectrum.

show abstract

Section: V-atpase –Related Lysosomal Acidification Failure In Diseasementioning

confidence: 99%

Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease

Colacurcio

Nixon

2016

Ageing Research Reviews

401

329

View full text Add to dashboard Cite

show abstract

“…Dysfunctions of these subunits manifest in osteopetrosis or osteopetrosis-related changes. The mechanisms involve changes in extracellular acidification, a fusion of preosteoclasts, and cytoskeletal F-actin assembly of osteoclasts 3, 8, 11, 17, 28, 29. In this context, we expected that defects in ATP6V1H would impair osteoclast function; indeed, we discovered that ATP6V1H was highly expressed in osteoclasts and the expression level of ATP6V1H was decreased in Atp6v1h +/- osteoclasts.…”

Section: Discussionmentioning

confidence: 94%

“…The V 1 B2 subunit of V-ATPase is associated with F-actin and facilitates the recruitment of V-ATPase complexes to the osteoclast ruffled border during polarization and bone resorption 15, 16. Recent findings have shown that mutations in the ATP6V1B1 gene cause Zimmermann-Laband syndrome and dominant deafness-onychodystrophy syndrome, which might be related to impaired assembly of the V 1 subcomplex of ATP6V 1B1 17, 18.…”

Section: Introductionmentioning

confidence: 99%

Deficiency of ATP6V1H Causes Bone Loss by Inhibiting Bone Resorption and Bone Formation through the TGF-β1 Pathway

et al. 2016

View full text Add to dashboard Cite

Vacuolar-type H +-ATPase (V-ATPase) is a highly conserved, ancient enzyme that couples the energy of ATP hydrolysis to proton transport across vesicular and plasma membranes of eukaryotic cells. Previously reported mutations of various V-ATPase subunits are associated with increased bone density. We now show that haploinsufficiency for the H subunit of the V1 domain (ATP6V1H) is associated with osteoporosis in humans and mice. A genome-wide SNP array analysis of 1625 Han Chinese found that 4 of 15 tag SNPs (26.7%) within ATP6V1H were significantly associated with low spine bone mineral density. Atp6v1h+/- knockout mice generated by the CRISPR/Cas9 technique had decreased bone remodeling and a net bone matrix loss. Atp6v1h+/- osteoclasts showed impaired bone formation and increased bone resorption. The increased intracellular pH of Atp6v1h+/- osteoclasts downregulated TGF-β1 activation, thereby reducing induction of osteoblast formation but the bone mineralization was not altered. However, bone formation was reduced more than bone resorption. Our data provide evidence that partial loss of ATP6V1H function results in osteoporosis/osteopenia. We propose that defective osteoclast formation triggers impaired bone formation by altering bone remodeling. In the future, ATP6V1H might, therefore, serve as a target for the therapy of osteoporosis.

show abstract

“…Sequencing revealed a homozygous ATP6VOA4 mutation (c.1185delC; p.Y396TfsX12) in both sibs, explaining their renal tubular acidosis and hearing loss [46]. Exome sequencing identified homozygous, predicted deleterious mutations in SLC52A2 (c.1327T>C; p.C443R) in both affected siblings; mutations in this riboflavin transporter are associated with Brown-Vialetto-van Laere syndrome type 2, a progressive neurologic disorder with deafness, bulbar dysfunction, and axial and limb hypotonia [47]; the children were treated with riboflavin.…”

Section: Insights From the Udpmentioning

confidence: 99%

The NIH Undiagnosed Diseases Program and Network: Applications to modern medicine

Gahl

Mulvihill

Toro

et al. 2016

Molecular Genetics and Metabolism

154

122

View full text Add to dashboard Cite

Introduction The inability of some seriously and chronically ill individuals to receive a definitive diagnosis represents an unmet medical need. In 2008, the NIH Undiagnosed Diseases Program (UDP) was established to provide answers to patients with mysterious conditions that long eluded diagnosis and to advance medical knowledge. Patients admitted to the NIH UDP undergo a five-day hospitalization, facilitating highly collaborative clinical evaluations and a detailed, standardized documentation of the individual’s phenotype. Bedside and bench investigations are tightly coupled. Genetic studies include commercially available testing, single nucleotide polymorphism microarray analysis, and family exomic sequencing studies. Selected gene variants are evaluated by collaborators using informatics, in vitro cell studies, and functional assays in model systems (fly, zebrafish, worm, or mouse). Insights from the UDP In seven years, the UDP received 2954 complete applications and evaluated 863 individuals. Nine vignettes (two unpublished) illustrate the relevance of an undiagnosed diseases program to complex and common disorders, the coincidence of multiple rare single gene disorders in individual patients, newly recognized mechanisms of disease, and the application of precision medicine to patient care. Conclusions The UDP provides examples of the benefits expected to accrue with the recent launch of a national Undiagnosed Diseases Network (UDN). The UDN should accelerate rare disease diagnosis and new disease discovery, enhance the likelihood of diagnosing known diseases in patients with uncommon phenotypes, improve management strategies, and advance medical research.

show abstract

De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome

Cited by 59 publications

References 11 publications

Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease

Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease

Deficiency of ATP6V1H Causes Bone Loss by Inhibiting Bone Resorption and Bone Formation through the TGF-β1 Pathway

The NIH Undiagnosed Diseases Program and Network: Applications to modern medicine

Contact Info

Product

Resources

About