Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome

Kortüm, Fanny; Caputo, Viviana; Bauer, Christiane K.; Stella, Lorenzo; Ciolfi, Andrea; Alawi, Malik; Bocchinfuso, Gianfranco; Flex, Elisabetta; Paolacci, Stefano; Dentici, Maria Lisa; Grammatico, Paola; Korenke, Georg Christoph; Leuzzi, Vincenzo; Mowat, David; Nair, Lal Devayani Vasudevan; Nguyen, Thi Tuyet Mai; Thierry, Patrick; White, Susan; Dallapiccola, Bruno; Pizzuti, Antonio; Campeau, Philippe M.; Tartaglia, Marco; Kutsche, Kerstin

doi:10.1038/ng.3282

Cited by 177 publications

(230 citation statements)

References 59 publications

(57 reference statements)

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“…Mice lacking V1B1 display upregulation of the homologous V1B2 isoform (Vedovelli et al, 2013), suggesting a compensatory mechanism to promote v-ATPase assembly when certain v-ATPase components are lost. Mutations in the v-ATPase subunit V1B2, the brain-specific isoform of the V1B subunit, are found in Dominant deafness-onychodystrophy syndrome and Zimmermann-Laband syndrome, two very rare genetic disorders (Kortum et al, 2015). Besides sharing features of deafness (reversible via cochlear implant) and digital abnormalities, the latter syndrome causes intellectual disability.…”

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

378

329

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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.

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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

378

329

View full text Add to dashboard Cite

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“…org/gatk/guide/best-practices). Called variants were filtered as previously reported (Cordeddu et al 2014;Niceta et al 2015;Kortum et al 2015). The predicted functional effect of variants was annotated with SnpEff toolbox V.4.…”

Section: Whole Exome Sequencingmentioning

confidence: 99%

“…Only variants with a predicted effect on the coding sequence, located in exons and splice sites (intronic variants located from −5 to +5 with respect to an exon-intron junction) were considered. Functional annotation of variants was performed using SnpEff V.4 and dbNSFP V. 2.8 (Cordeddu et al 2014;Niceta et al 2015;Kortum et al 2015).…”

Section: Whole Exome Sequencingmentioning

confidence: 99%

Expanding the molecular diversity and phenotypic spectrum of glycerol 3‐phosphate dehydrogenase 1 deficiency

Dionisi‐Vici

Shteyer

Niceta

et al. 2016

J of Inher Metab Disea

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Transient infantile hypertriglyceridemia (HTGT1; OMIM #614480) is a rare autosomal recessive disorder, which manifests in early infancy with transient hypertriglyceridemia, hepatomegaly, elevated liver enzymes, persistent fatty liver and hepatic fibrosis. This rare clinical entity is caused by inactivating mutations in the GPD1 gene, which encodes the cytosolic isoform of glycerol-3-phosphate dehydrogenase. Here we report on four patients from three unrelated families of diverse ethnic origins, who presented with hepatomegaly, liver steatosis, hypertriglyceridemia, with or without fasting ketotic hypoglycemia. Whole exome sequencing revealed the affected individuals to harbor deleterious biallelic mutations in the GPD1 gene, including the previously undescribed c.806G > A (p.Arg269Gln) and c.640T > C (p.Cys214Arg) mutations. The clinical features in three of our patients showed several differences compared to the original reports. One subject presented with recurrent episodes of fasting hypoglycemia along with hepatomegaly, hypetriglyceridemia, and elevated liver enzymes; the second showed a severe liver disease, with intrahepatic cholestasis associated with kidney involvement; finally, the third presented persistent hypertriglyceridemia at the age of 30 years. These findings expand the current knowledge of this rare disorder, both with regard to the phenotype and molecular basis. The enlarged phenotypic spectrum of glycerol-3-phosphate dehydrogenase 1 deficiency can mimic other inborn errors of metabolism with liver involvement and should alert clinicians to recognize this entity by considering GPD1 mutations in appropriate clinical settings.

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“…We pooled equal amounts of DNA from the four affected individuals 3, 4, 10, and 11 ( Fig. 1) and used this single genomic DNA probe to perform targeted enrichment and massively parallel sequencing as described previously [Kort€ um et al, 2015;Van Rahden et al, 2015]. Whole exome enrichment was performed using Nextera 1 Exome Enrichment Kit (62 Mb) (Illumina, San Diego, CA) according to the manufacturer's protocols.…”

Section: Whole Exome Sequencing (Wes) and Data Analysismentioning

confidence: 99%

Homozygous HOXB1 loss‐of‐function mutation in a large family with hereditary congenital facial paresis

Vogel

Velleuer

Schmidt-Jiménez

et al. 2016

American J of Med Genetics Pt A

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Hereditary congenital facial paresis (HCFP) belongs to the congenital cranial dysinnervation disorders. HCFP is characterized by the isolated dysfunction of the seventh cranial nerve and can be associated with hearing loss, strabismus, and orofacial anomalies. Möbius syndrome shares facial palsy with HCFP, but is additionally characterized by limited abduction of the eye(s). Genetic heterogeneity has been documented for HCFP as one locus mapped to chromosome 3q21-q22 (HCFP1) and a second to 10q21.3-q22.1 (HCFP2). The only known causative gene for HCFP is HOXB1 (17q21; HCFP3), encoding a homeodomain-containing transcription factor of the HOX gene family, which are master regulators of early developmental processes. The previously reported HOXB1 mutations change arginine 207 to another residue in the homeodomain and alter binding capacity of HOXB1 for transcriptional co-regulators and DNA. We performed whole exome sequencing in HCFP-affected individuals of a large consanguineous Moroccan family. The homozygous nonsense variant c.66C>G/p.(Tyr22*) in HOXB1 was identified in the four patients with HCFP and ear malformations, while healthy family members carried the mutation in the heterozygous state. This is the first disease-associated HOXB1 mutation with a likely loss-of-function effect suggesting that all HOXB1 variants reported so far also have severe impact on activity of this transcriptional regulator. © 2016 Wiley Periodicals, Inc.

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Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome

Cited by 177 publications

References 59 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

Expanding the molecular diversity and phenotypic spectrum of glycerol 3‐phosphate dehydrogenase 1 deficiency

Homozygous HOXB1 loss‐of‐function mutation in a large family with hereditary congenital facial paresis

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