Phenotypic spectrum associated with CASK loss-of-function mutations

Moog, Ute; Kutsche, Kerstin; Kortüm, Fanny; Chilian, Bettina; Bierhals, Tatjana; Apeshiotis, Neophytos; Balg, Stefanie; Chassaing, Nicolas; Coubes, Christine; Das, Soma; Engels, Hartmut; Esch, Hilde Van; Grasshoff, Ute; Heise, Marisol; Isidor, Bertrand; Jarvis, Joanna; Koehler, Udo; Martin, Thomas G.; Oehl-Jaschkowitz, Barbara; Ortibus, Els; Pilz, Daniela T.; Prabhakar, P; Rappold, Gudrun; Rau, Isabella; Rettenberger, G.; Schlüter, Gregor; Scott, Richard; Shoukier, Moonef; Wohlleber, Eva; Zirn, Birgit; Dobyns, William B.; Uyanık, Gökhan

doi:10.1136/jmedgenet-2011-100218

Cited by 125 publications

(182 citation statements)

References 18 publications

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“…52 A recent study reported renal/urologic anomalies, including fusion of kidneys, unilateral kidney ectasia, and malrotated kidney, in patients with CASK loss-of-function mutations. 53 Although these defects did not include our DKO phenotype of renal hypoplasia, they do suggest that scaffolding proteins may play an important role in congenital anomalies of the kidney and urinary tract (CAKUT). Because deletion of Cask alone in mouse nephron progenitors did not result in a kidney phenotype, we speculate that the renal anomaly observed in humans is the result of a combined effect with a variation in a protein that interacts with CASK, such as DLG1, Scribble, or the Lethal Giant Larvae homolog.…”

Section: Discussionmentioning

confidence: 99%

Scaffolding Proteins DLG1 and CASK Cooperate to Maintain the Nephron Progenitor Population during Kidney Development

Ahn

Kim²,

Swat³

et al. 2013

Journal of the American Society of Nephrology

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DLG1 (discs-large homolog 1) and CASK (calcium/calmodulin-dependent serine protein kinase) interact at membrane-cytoskeleton interfaces and function as scaffolding proteins that link signaling molecules, receptors, and other scaffolding proteins at intercellular and synaptic junctions. Dlg1-null mice exhibit hydronephrosis, hydroureter, and occasionally hypoplastic kidneys, whereas Cask-null mice do not. To investigate whether DLG1 and CASK cooperate in the developing urogenital system, we generated mice deficient in both DLG1 and CASK either 1) globally, 2) in metanephric mesenchyme, or 3) in nephron progenitors. With each approach, Dlg1;Cask double-knockout (DKO) kidneys were severely hypoplastic and dysplastic and demonstrated rapid, premature depletion of nephron progenitors/stem cells. Several cellular and molecular defects were observed in the DKO kidneys, including reduced proliferation and increased apoptosis of cells in the nephrogenic zone and a progressive decrease in the number of cells expressing SIX2, a transcription factor essential for maintaining nephron progenitors. Fgf8 expression was reduced in early-stage DKO metanephric mesenchyme, accompanied by reduced levels of components of the Ras pathway, which is activated by fibroblast growth factor (FGF) signaling. Moreover, Dlg1 +/2 ; Cask 2/2 (het/null) kidneys were moderately hypoplastic and demonstrated impaired aggregation of SIX2-positive cells around the ureteric bud tips. Nephron progenitor-specific het/null mice survived with small kidneys but developed glomerulocystic kidney disease and renal failure. Taken together, these results suggest that DLG1 and CASK play critical cooperative roles in maintaining the nephron progenitor population, potentially via a mechanism involving effects on FGF signaling.

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Section: Discussionmentioning

confidence: 99%

Scaffolding Proteins DLG1 and CASK Cooperate to Maintain the Nephron Progenitor Population during Kidney Development

Ahn

Kim²,

Swat³

et al. 2013

Journal of the American Society of Nephrology

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show abstract

“…Her neuroimaging demonstrates hypoplasia of the pons and cerebellar vermis, bowing and thinning of the corpus callosum, mild cerebral atrophy and dysplastic amygdala and hippocampi. This constellation of brain findings is reminiscent of the neurodevelopmental phenotype due to mutations in the CASK gene [Moog et al, 2011].…”

Section: Introductionmentioning

confidence: 99%

Brain malformations in a patient with deletion 2p16.1: A refinement of the phenotype to BCL11A

Balci

Sawyer

Dávila

et al. 2015

European Journal of Medical Genetics

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“…2,3 Calcium/calmodulin-dependent serine protein kinase (CASK) is one of the X-linked genes associated with syndromic mental retardation. [4][5][6][7][8][9] CASK mutations identified from patients are widely distributed across the entire gene, and no hot mutation spot in CASK linked to the disorder has been identified. 7,10 The phenotypes of patients with CASK mutations also vary.…”

Section: Introductionmentioning

confidence: 99%

Calcium/calmodulin-dependent serine protein kinase (CASK), a protein implicated in mental retardation and autism-spectrum disorders, interacts with T-Brain-1 (TBR1) to control extinction of associative memory in male mice

Huang

Hsueh

2017

JPN

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Phenotypic spectrum associated with CASK loss-of-function mutations

Abstract: These findings define the phenotypic spectrum associated with CASK loss-of-function mutations. The combination of developmental and brain imaging features together with mild facial dysmorphism is highly suggestive of this disorder and should prompt subsequent testing of the CASK gene.

Cited by 125 publications

References 18 publications

Scaffolding Proteins DLG1 and CASK Cooperate to Maintain the Nephron Progenitor Population during Kidney Development

Scaffolding Proteins DLG1 and CASK Cooperate to Maintain the Nephron Progenitor Population during Kidney Development

Brain malformations in a patient with deletion 2p16.1: A refinement of the phenotype to BCL11A

Calcium/calmodulin-dependent serine protein kinase (CASK), a protein implicated in mental retardation and autism-spectrum disorders, interacts with T-Brain-1 (TBR1) to control extinction of associative memory in male mice

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