Phenotypic and functional consequences of haploinsufficiency of genes from exocyst and retinoic acid pathway due to a recurrent microdeletion of 2p13.2

Wen, Jiadi; Lopes, Fátima; Soares, Gabriela; Farrell, Sandra A.; Nelson, Cara; Qiao, Ying; Martell, Sally; Badukke, Chansonette; Bessa, Carlos; Ylstra, Bauke; Sm, Lewis; Isoherranen, Nina; Maciel, Patrı́cia; Rajcan‐Separovic, Evica

doi:10.1186/1750-1172-8-100

Cited by 23 publications

(25 citation statements)

References 52 publications

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“…Although disruption of MUNC18-1 is most closely associated with Ohtahara syndrome, de novo mutations in MUNC18-1 have also been identified in individuals with severe intellectual disability and non-syndromic epilepsy, individuals with non-syndromic intellectual disability, and individuals with Rett syndrome (Hamdan et al, 2011(Hamdan et al, , 2009Olson et al, 2015;Romaniello et al, 2015). Likewise, recent studies have revealed possible connections between mutations in exocyst genes and neurological disorders (Evers et al, 2014;Frühmesser et al, 2013;Wen et al, 2013). Given that dendrite defects are the strongest pathological correlate of intellectual disability (Kaufmann and Moser, 2000), we speculate that dendritic abnormalities might contribute to intellectual disability that is associated with MUNC18-1 and exocyst dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Regulation of dendrite growth and maintenance by exocytosis

Peng

Lee

Rowland

et al. 2015

Journal of Cell Science

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Dendrites lengthen by several orders of magnitude during neuronal development, but how membrane is allocated in dendrites to facilitate this growth remains unclear. Here, we report that Ras opposite (Rop), the Drosophila ortholog of the key exocytosis regulator Munc18-1 (also known as STXBP1), is an essential factor mediating dendrite growth. Neurons with depleted Rop function exhibit reduced terminal dendrite outgrowth followed by primary dendrite degeneration, suggestive of differential requirements for exocytosis in the growth and maintenance of different dendritic compartments. Rop promotes dendrite growth together with the exocyst, an octameric protein complex involved in tethering vesicles to the plasma membrane, with Rop-exocyst complexes and exocytosis predominating in primary dendrites over terminal dendrites. By contrast, membrane-associated proteins readily diffuse from primary dendrites into terminals, but not in the reverse direction, suggesting that diffusion, rather than targeted exocytosis, supplies membranous material for terminal dendritic growth, revealing key differences in the distribution of materials to these expanding dendritic compartments.

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Section: Discussionmentioning

confidence: 99%

Regulation of dendrite growth and maintenance by exocytosis

Peng

Lee

Rowland

et al. 2015

Journal of Cell Science

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“…[9][10][11][12] EXOC6B haploinsufficiency has been suggested as a cause for intellectual disability (ID). 10 A homozygous loss-of-function EXOC6B variant in siblings with a skeletal disorder and heterozygosity of the same in healthy parents contrast with the literature.…”

Section: Resultsmentioning

confidence: 99%

A novel multiple joint dislocation syndrome associated with a homozygous nonsense variant in the EXOC6B gene

et al. 2015

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We report two brothers from a consanguineous couple with spondyloepimetaphyseal dysplasia (SEMD), multiple joint dislocations at birth, severe joint laxity, scoliosis, gracile metacarpals and metatarsals, delayed bone age and poorly ossified carpal and tarsal bones, probably representing a yet uncharacterized SEMD with laxity and dislocations. This condition has clinical overlap with autosomal dominantly inherited SEMD with joint laxity, leptodactylic type caused by recurrent missense variants in the kinesin family member 22 gene (KIF22). Single-nucleotide polymorphism array analysis and whole-exome sequencing in the two affected siblings revealed a shared homozygous nonsense variant [c.906T4A/p.(Tyr302*)] in EXOC6B as the most likely cause. EXOC6B encodes a component of the exocyst complex required for tethering secretory vesicles to the plasma membrane. As transport of vesicles from the golgi apparatus to the plasma membrane occurs through kinesin motor proteins along microtubule tracks, the function of EXOC6B is linked to KIF22 suggesting a common pathogenic mechanism in skeletal dysplasias with joint laxity and dislocations. INTRODUCTIONSkeletal dysplasias with multiple joint dislocations is a heterogeneous group of disorders comprising~10 distinct entities. 1 Spondyloepimetaphyseal dysplasia (SEMD) with joint laxity type 2 (leptodactylic type, Hall type or SEMD-JL2; MIM 603546) is an autosomal dominant skeletal dysplasia with short stature, multiple joint dislocations and/or laxity, delayed ossification of carpals, small carpus, severe epiphyseal and mild metaphyseal changes, mild vertebral body deformities and gracile metacarpals. 2 Missense variants affecting one of two amino acids in the motor domain of the kinesin family member KIF22 have been identified to cause SEMD-JL2. 3,4 Key features of SEMD with joint laxity, type 1, with or without fractures (SEMD-JL1; MIM 271640), which is caused by biallelic variants in B3GALT6, 5,6 are joint laxity and dislocations and SEMD. Affected individuals show facial dysmorphism, kyphoscoliosis at birth, talipes equinovarus, cleft palate and congenital heart disease. 7 Another SEMD-JL2-like phenotype is associated with a homozygous missense variant in NIN. 8 Here, we report two brothers with a new type of autosomal recessive SEMD with laxity and joint dislocations. We used single-nucleotide polymorphism (SNP) array analysis and whole-exome sequencing (WES) to identify a homozygous nonsense variant in EXOC6B in the affected siblings.

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“…Wen et al reported partially overlapping microdeletions involving 2p13.2 in two boys with ID, hyperactivity, ear malformations, and vertebral and/or craniofacial abnormalities [Wen et al, 2013]. One of the patients had a de novo 4 Mb deletion of 2p13.1-p13.3 comprising EXOC6B and 61 other genes.…”

Section: Discussionmentioning

confidence: 99%

“…One of the patients had a de novo 4 Mb deletion of 2p13.1-p13.3 comprising EXOC6B and 61 other genes. The other one (Patient 1 in Wen et al, 2013) had a small de novo deletion of 0.78 Mb at 2p13.2-13.3 (bp positions converted to hg19: 72,287,071,118) including only two genes: EXOC6B and CYP26B1 (Fig. 2).…”

Section: Discussionmentioning

confidence: 99%

“…Functional studies in this patient showed reduced mRNA expression of CYP26B1, EXOC6B and its downstream effector HES1. Since complete loss of CYP26B1 has been associated with multiple skeletal defects in mice, zebrafish and humans Wen et al assumed that the deletion of CYP26B1 may contribute to the skeletal and craniofacial abnormalities seen in their patient [Maclean et al, 2009;Laue et al, 2011;Wen et al, 2013]. However, apparently healthy heterozygous carriers of a CYP26B mutation have been described [Laue et al, 2011].…”

Section: Discussionmentioning

confidence: 99%

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Mosaic deletion of EXOC6B: Further evidence for an important role of the exocyst complex in the pathogenesis of intellectual disability

Evers

Maas

Koch

et al. 2014

American J of Med Genetics Pt A

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We describe a boy with developmental delay, speech delay, and minor dysmorphic features with a heterozygous de novo ∼460 kb deletion at 2p13.2 involving only parts of EXOC6B present in about 50% of lymphocytes. This widely expressed gene encodes the exocyst component 6B, which is part of a multiprotein complex required for targeted exocytosis. Little is known about the effect of EXOC6B haploinsufficiency. In 2008, a patient with a complex syndromic phenotype, including left renal agenesis, neutropenia, recurrent pulmonary infections, long bone diaphysis broadening, growth retardation, and developmental delay (DD) was found to carry a de novo translocation t(2;7) involving TSN3 and EXOC6B. Further characterization of the translocation indicated that disruption of TSN3 may be responsible for the skeletal phenotype. Recently, a heterozygous deletion of EXOC6B along with a deletion of the CYP26B1 gene has been reported in a boy with intellectual disability, speech delay, hyperactivity, facial asymmetry, a dysplastic ear, brachycephaly, and mild joint contractures. Additionally, disruption of EXOC6B by a de novo balanced translocation t(2;8) has been described in a patient with developmental delay, epilepsy, autistic and aggressive behavior. This is the first report of a de novo deletion affecting only EXOC6B in an individual with developmental delay. In conclusion, based on our findings and recent data from the literature, there is evidence that EXOC6B and the exocyst complex might play an important role in the molecular pathogenesis of intellectual disability.

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Phenotypic and functional consequences of haploinsufficiency of genes from exocyst and retinoic acid pathway due to a recurrent microdeletion of 2p13.2

Cited by 23 publications

References 52 publications

Regulation of dendrite growth and maintenance by exocytosis

Regulation of dendrite growth and maintenance by exocytosis

A novel multiple joint dislocation syndrome associated with a homozygous nonsense variant in the EXOC6B gene

Mosaic deletion of EXOC6B: Further evidence for an important role of the exocyst complex in the pathogenesis of intellectual disability

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