Recessive Mutations in DOCK6, Encoding the Guanidine Nucleotide Exchange Factor DOCK6, Lead to Abnormal Actin Cytoskeleton Organization and Adams-Oliver Syndrome

Shaheen, Ranad; Faqeih, Eissa; Sunker, Asma; Morsy, Heba; Al‐Sheddi, Tarfa; Shamseldin, Hanan E.; Adly, Nouran; Alkuraya, Fowzan S.

doi:10.1016/j.ajhg.2011.07.009

Cited by 116 publications

(123 citation statements)

References 38 publications

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“…The phenotypes of mice lacking Dock7, generalized hypopigmentation and white-spotting (33), are not seen in Angptl3 −/− mice. Mutations in DOCK6 cause Adams-Oliver syndrome, a rare disorder affecting skin and limb development, without noted changes in plasma lipid levels (34). Mice lacking Angptl8 were hypotriglyceridemic but no other notable phenotype was observed in a broad phenotypic screen (32).…”

Section: Discussionmentioning

confidence: 99%

Atypical angiopoietin-like protein that regulates ANGPTL3

Quagliarini

Wang

Kozlitina

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

402

655

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Angiopoietin-like proteins (ANGPTLs) play major roles in the trafficking and metabolism of lipids. Inactivation of ANGPTL3, a gene located in an intron of DOCK7, results in very low levels of LDL-cholesterol (C), HDL-C and triglyceride (TAG). We identified another ANGPTL family member, ANGPTL8, which is located in the corresponding intron of DOCK6. A variant in this family member (rs2278426, R59W) was associated with lower plasma LDL-C and HDL-C levels in three populations. ANGPTL8 is expressed in liver and adipose tissue, and circulates in plasma of humans. Expression of ANGPTL8 was reduced by fasting and increased by refeeding in both mice and humans. To examine the functional relationship between the two ANGPTL family members, we expressed ANGPTL3 at physiological levels alone or together with ANGPTL8 in livers of mice. Plasma TAG level did not change in mice expressing ANGPTL3 alone, whereas coexpression with ANGPTL8 resulted in hypertriglyceridemia, despite a reduction in circulating ANGPTL3. ANGPTL8 coimmunoprecipitated with the N-terminal domain of ANGPTL3 in plasma of these mice. In cultured hepatocytes, ANGPTL8 expression increased the appearance of N-terminal ANGPTL3 in the medium, suggesting ANGPTL8 may activate ANGPTL3. Consistent with this scenario, expression of ANGPTL8 in Angptl3 −/− mice failed to promote hypertriglyceridemia. Thus, ANGPTL8, a paralog of ANGPTL3 that arose through duplication of an ancestral DOCK gene, regulates postprandial TAG and fatty acid metabolism by controlling activation of its progenitor, and perhaps other ANGPTLs. Inhibition of ANGPTL8 provides a new therapeutic strategy for reducing plasma lipoprotein levels.T he angiopoietin-like (ANGPTL) genes encode a family of secreted proteins with pleiotropic effects on vascular cells (1), lipid metabolism (2), and stem cell biology (3). The family members share a common architecture, comprising an extended N-terminal domain and a C-terminal fibrinogen-like domain. Genetic studies have revealed that two closely related family members, ANGPTL3 and ANGPTL4, play pivotal roles in the trafficking and metabolism of lipids and lipoproteins (4-7). Mutations that disrupt ANGPTL3 are associated with greatly reduced plasma levels of triacylglycerol (TAG) and cholesterol in mice (5) and in humans (4). Mice lacking ANGPTL4 also have markedly reduced levels of plasma TAG and cholesterol (8, 9), and sequence variations in ANGPTL4 are associated with lower plasma TAG levels in humans (7).TAG synthesized in the gut and liver are incorporated into chylomicrons and very low density lipoproteins (VLDL), respectively, and delivered to peripheral tissues where they interact with lipoprotein lipase (LPL). LPL hydrolyzes the TAGs, releasing fatty acids to the adjacent tissues. Other intravascular lipases, including hepatic lipase and endothelial lipase, further remodel lipoprotein particles. Several lines of evidence suggest that ANGPTL3 and ANGPTL4 contribute to the partitioning of TAGs among tissues (2). During fasting, ANGPTL4 levels increase in ad...

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Section: Discussionmentioning

confidence: 99%

Atypical angiopoietin-like protein that regulates ANGPTL3

Quagliarini

Wang

Kozlitina

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

402

655

View full text Add to dashboard Cite

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“…Yamaguchi et al 56 Glazov et al 57 Puente et al 58 Gunay-Aygun et al 59 Weedon et al 60 Homozygosity (Figure 3b Becker et al 31 Walsh et al 35 Wang et al 51a Bolze et al 61 Caliskan et al 62 Bilguvar et al 63 O'Sullivan et al 64 Barak et al 65 Hanson et al 66 Shaheen et al 67 Doi et el Only a single experiment is required.…”

Section: Affecting Protein Sequencementioning

confidence: 99%

Disease gene identification strategies for exome sequencing

et al. 2012

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“…As we have shown previously, autozygome served as an extremely powerful filter of the resulting variants. 35,36 In Family MKS_F1, two variants survived filtration but TMEM237 was recently described as a novel Joubert gene. 25 Some of the original reported cases had occipital encephalocele and cystic kidney so it seems likely that our mutation is the causal variant.…”

Section: Head and Neckmentioning

confidence: 99%

Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

et al. 2012

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Meckel-Gruber syndrome (MKS, OMIM #249000) is a multiple congenital malformation syndrome that represents the severe end of the ciliopathy phenotypic spectrum. Despite the relatively common occurrence of this syndrome among Arabs, little is known about its genetic architecture in this population. This is a series of 18 Arab families with MKS, who were evaluated clinically and studied using autozygome-guided mutation analysis and exome sequencing. We show that autozygome-guided candidate gene analysis identified the underlying mutation in the majority (n ¼ 12, 71%). Exome sequencing revealed a likely pathogenic mutation in three novel candidate MKS disease genes. These include C5orf42, Ellis-van-Creveld disease gene EVC2 and SEC8 (also known as EXOC4), which encodes an exocyst protein with an established role in ciliogenesis. This is the largest and most comprehensive genomic study on MKS in Arabs and the results, in addition to revealing genetic and allelic heterogeneity, suggest that previously reported disease genes and the novel candidates uncovered by this study account for the overwhelming majority of MKS patients in our population.

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Recessive Mutations in DOCK6, Encoding the Guanidine Nucleotide Exchange Factor DOCK6, Lead to Abnormal Actin Cytoskeleton Organization and Adams-Oliver Syndrome

Cited by 116 publications

References 38 publications

Atypical angiopoietin-like protein that regulates ANGPTL3

Atypical angiopoietin-like protein that regulates ANGPTL3

Disease gene identification strategies for exome sequencing

Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

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