Mutation of Murine Adenylate Kinase 7 Underlies a Primary Ciliary Dyskinesia Phenotype

Fernandez-Gonzalez, Angeles; Kourembanas, Stella; Wyatt, Todd A.; Mitsialis, S. Alex

doi:10.1165/rcmb.2008-0102oc

Cited by 73 publications

(95 citation statements)

References 48 publications

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“…Ak7 (adenylate kinase 7): 30,66,71 Our findings were essentially identical to those recently reported by another group. 30 Grossly, all Ak7 -/-mutant mice exhibited domed heads and hydrocephalus.…”

Section: Ulk4 (Unc-51-like Kinase 4 [C Elegans])supporting

confidence: 92%

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Congenital Hydrocephalus in Genetically Engineered Mice

et al. 2011

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There is evidence that genetic factors play a role in the complex multifactorial pathogenesis of hydrocephalus. Identification of the genes involved in the development of this neurologic disorder in animal models may elucidate factors responsible for the excessive accumulation of cerebrospinal fluid in hydrocephalic humans. The authors report here a brief summary of findings from 12 lines of genetically engineered mice that presented with autosomal recessive congenital hydrocephalus. This study illustrates the value of knockout mice in identifying genetic factors involved in the development of congenital hydrocephalus. Findings suggest that dysfunctional motile cilia represent the underlying pathogenetic mechanism in 8 of the 12 lines (Ulk4, Nme5, Nme7, Kif27, Stk36, Dpcd, Ak7, and Ak8). The likely underlying cause in the remaining 4 lines (RIKEN 4930444A02, Celsr2, Mboat7, and transgenic FZD3) was not determined, but it is possible that some of these could also have ciliary defects. For example, the cerebellar malformations observed in RIKEN 4930444A02 knockout mice show similarities to a number of developmental disorders, such as Joubert, Meckel-Gruber, and Bardet-Biedl syndromes, which involve mutations in ciliarelated genes. Even though the direct relevance of mouse models to hydrocephalus in humans remains uncertain, the high prevalence of familial patterns of inheritance for congenital hydrocephalus in humans suggests that identification of genes responsible for development of hydrocephalus in mice may lead to the identification of homologous modifier genes and susceptibility alleles in humans. Also, characterization of mouse models can enhance understanding of important cell signaling and developmental pathways involved in the pathogenesis of hydrocephalus.

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Section: Ulk4 (Unc-51-like Kinase 4 [C Elegans])supporting

confidence: 92%

“…30 Grossly, all Ak7 -/-mutant mice exhibited domed heads and hydrocephalus. Histologically, the most notable lesions included moderate to severe hydrocephalus, which was accompanied by chronic active rhinosinusitis characterized -/-mouse.…”

Section: Ulk4 (Unc-51-like Kinase 4 [C Elegans])mentioning

confidence: 98%

Congenital Hydrocephalus in Genetically Engineered Mice

et al. 2011

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“…37 Three AKs are now known to be associated with disease phenotypes, AK1 (OMIM 103000) causes chronic hemolytic anemia in humans, 38 AK2 (OMIM 267500) causes reticular dysgenesis in humans, 39 and AK7 (OMIM 615364) with primary ciliary dyskinesia in mice. 40 AK1, like AK9, is cytosolic and associated with mental retardation and psychomotor retardation. Taken together, AKs are disease genes and associated with specific phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Limb girdle myasthenia with digenic RAPSN and a novel disease gene AK9 mutations

et al. 2016

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Though dysfunction of neuromuscular junction (NMJ) is associated with congenital myasthenic syndrome (CMS), the proteins involved in neuromuscular transmission have not been completely identified. In this study, we aimed to identify a novel CMS gene in a consanguineous family with limb-girdle type CMS. Homozygosity mapping of the novel CMS gene was performed using high-density single-nucleotide polymorphism microarrays. The variants in CMS gene were identified by whole-exome sequencing (WES) and Sanger sequencing. A 20 MB-region of homozygosity (ROH) was mapped on chromosome 6q15-21. This was the only ROH that present in all clinically affected siblings and absent in all clinically unaffected siblings. WES showed a novel variant of AK9 gene located in this ROH. This variant was a start-gain mutation and introduced a cryptic 5′-UTR signal in intron 5 of the AK9 gene. The normal splicing signal would be interfered by the cryptic translation signal leading to defective splicing. Another 25 MB-ROH was found on chromosome 11p13-q12 in all siblings. WES showed a homozygous RAPSN pathogenic variant in this ROH. Since RAPSN-associated limb-girdle type CMS was only manifested in AK9 homozygous variant carriers, the disease phenotype was of digenic inheritance, and was determined by the novel disease modifier AK9 which provides NTPs for N-glycosylation. This is the first time that this specific genotype-phenotype correlation is reported. Importantly, the AK9-associated nucleotide deficiency may replete by dietary supplements. Since AK9 is a disease modifier, enhancing N-glycosylation by increasing dietary nucleotides may be a new therapeutic option for CMS patients.

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“…Many studies have demonstrated motility as one of the main functions of cilia, and its impairment may cause severe phenotypes such as decreased ciliary beat frequency in the respiratory epithelium [13]. Ciliary motility is also required for brain development and function.…”

Section: Motility: Agents Of Cellular Movementmentioning

confidence: 99%