Genotype–phenotype relationship in three cases with overlapping 19p13.12 microdeletions

Bonaglia, María Clara; Marelli, Susan; Novara, Francesca; Commodaro, Simona; Borgatti, Renato; Minardo, Grazia; Memo, Luigi; Mangold, Elisabeth; Beri, Silvana; Zucca, Claudio; Brambilla, Daniele; Molteni, Massimo; Giorda, Roberto; Weber, Ruthild G.; Zuffardi, Orsetta

doi:10.1038/ejhg.2010.115

Cited by 47 publications

(65 citation statements)

References 30 publications

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“…In humans, one of the identified mutations leads to a potential truncated construct, preventing interaction with MyoVI. Also, a recent study correlated hearing impairment in four patients with a 359-kb deleted region in 19p13.12 harboring six genes, including GIPC1, leading the authors to suggest that haploinsufficiency of GIPC1 might contribute to hearing impairment through its interaction with MyoVI (Bonaglia et al, 2010). Altogether, these results strongly suggest that members of the GIPC family have essential roles in HC maturation and auditory function.…”

Section: Gipc1 Is a Regulator Of Hair Bundle Formation And Maintenancesupporting

confidence: 55%

Gipc1 has a dual role in Vangl2 trafficking and hair bundle integrity in the inner ear

Giese

Ezan

Wang³

et al. 2012

Development

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SUMMARYVangl2 is one of the central proteins controlling the establishment of planar cell polarity in multiple tissues of different species. Previous studies suggest that the localization of the Vangl2 protein to specific intracellular microdomains is crucial for its function. However, the molecular mechanisms that control Vangl2 trafficking within a cell are largely unknown. Here, we identify Gipc1 (GAIP C-terminus interacting protein 1) as a new interactor for Vangl2, and we show that a myosin VI-Gipc1 protein complex can regulate Vangl2 traffic in heterologous cells. Furthermore, we show that in the cochlea of MyoVI mutant mice, Vangl2 presence at the membrane is increased, and that a disruption of Gipc1 function in hair cells leads to maturation defects, including defects in hair bundle orientation and integrity. Finally, stimulated emission depletion microscopy and overexpression of GFP-Vangl2 show an enrichment of Vangl2 on the supporting cell side, adjacent to the proximal membrane of hair cells. Altogether, these results indicate a broad role for Gipc1 in the development of both stereociliary bundles and cell polarization, and suggest that the strong asymmetry of Vangl2 observed in early postnatal cochlear epithelium is mostly a 'tissue' polarity readout.

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Section: Gipc1 Is a Regulator Of Hair Bundle Formation And Maintenancesupporting

confidence: 55%

Gipc1 has a dual role in Vangl2 trafficking and hair bundle integrity in the inner ear

Giese

Ezan

Wang³

et al. 2012

Development

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show abstract

“…We note that mice deficient in Nfix function show, in addition to brain abnormalities, a kyphotic deformation of the spine and impairment of endochondral ossification in the vertebrae and femur. 15,16 There have been no reports of neoplasia in the condition to date. The small number of cases reported to date hinders identification of genotype-phenotype correlations for NFIX.…”

Section: Molecular Resultsmentioning

confidence: 99%

Malan syndrome: Sotos-like overgrowth with de novo NFIX sequence variants and deletions in six new patients and a review of the literature

et al. 2014

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De novo monoallelic variants in NFIX cause two distinct syndromes. Whole gene deletions, nonsense variants and missense variants affecting the DNA-binding domain have been seen in association with a Sotos-like phenotype that we propose is referred to as Malan syndrome. Frameshift and splice-site variants thought to avoid nonsense-mediated RNA decay have been seen in Marshall-Smith syndrome. We report six additional patients with Malan syndrome and de novo NFIX deletions or sequence variants and review the 20 patients now reported. The phenotype is characterised by moderate postnatal overgrowth and macrocephaly. Median height and head circumference in childhood are 2.0 and 2.3 standard deviations (SD) above the mean, respectively. There is overlap of the facial phenotype with NSD1-positive Sotos syndrome in some cases including a prominent forehead, high anterior hairline, downslanting palpebral fissures and prominent chin. Neonatal feeding difficulties and/or hypotonia have been reported in 30% of patients. Developmental delay/learning disability have been reported in all cases and are typically moderate. Ocular phenotypes are common, including strabismus (65%), nystagmus (25% ) and optic disc pallor/hypoplasia (25%). Other recurrent features include pectus excavatum (40%) and scoliosis (25%). Eight reported patients have a deletion also encompassing CACNA1A, haploinsufficiency of which causes episodic ataxia type 2 or familial hemiplegic migraine. One previous case had episodic ataxia and one case we report has had cyclical vomiting responsive to pizotifen. In individuals with this contiguous gene deletion syndrome, awareness of possible later neurological manifestations is important, although their penetrance is not yet clear.

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“…In humans, LPHN1 gene deletion has been linked to mental retardation, language delay, hyperactivity, hearing impairment, and cranial malformation (Bonaglia et al, 2010). Members of the ADGRB (BAI) subfamily have also been associated with human disease.…”

Section: Skeletal Muscle and Bonementioning

confidence: 99%

“…Presynaptic ADGRL1 (latrophilin-1) strongly binds postsynaptic teneurin-2, and this interaction regulates presynaptic Ca 2+ dynamics (Silva et al, 2011). Deletion of ADGRL1 (LPHN1), together with five other genes, leads to a neuropsychiatric syndromic disorder in humans (Bonaglia et al, 2010). Adgrl1 (Lphn1) knockout mice are viable, but demonstrate abnormal maternal behavior (Tobaben et al, 2002).…”

Section: Skeletal Muscle and Bonementioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein–Coupled Receptors

et al. 2015

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Genotype–phenotype relationship in three cases with overlapping 19p13.12 microdeletions

Cited by 47 publications

References 30 publications

Gipc1 has a dual role in Vangl2 trafficking and hair bundle integrity in the inner ear

Gipc1 has a dual role in Vangl2 trafficking and hair bundle integrity in the inner ear

Malan syndrome: Sotos-like overgrowth with de novo NFIX sequence variants and deletions in six new patients and a review of the literature

International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein–Coupled Receptors

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