Variability in expression of a familial 2.79 Mb microdeletion in chromosome14q22.1–22.2

Lumaka, Aimé; Hole, C. Van; Casteels, Ingele; Ortibus, Els; Wolf, Veerle De; Vermeesch, Joris Robert; Lukusa, T; Devriendt, Koen

doi:10.1002/ajmg.a.35353

Cited by 18 publications

(23 citation statements)

References 26 publications

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“…Here, we identify two evolutionarily conserved regions 5′, and one 3′, of the six6 coding region, which independently control the late and early expression of six6 , respectively. We find the early enhancer is not only sufficient for eye field and optic vesicle expression of six6 , but also required for normal optic vesicle size, which is consistent with the established role for Six6 in regulating eye size, not only in animal models but also human patients (Aldahmesh et al, 2013; Bar-Yosef et al, 2004; Bennett et al, 1991; Cheng et al, 2015; Dixit et al, 2014; Fish et al, 2014; Fuhrmann et al, 2000; Lee et al, 2012; Lumaka et al, 2012; Nojima et al, 2010; Toy et al, 1998; Yariz et al, 2015; Zuber et al, 1999). The identification of distinct regions that function modularly, to independently control eye field/optic vesicle versus optic cup/mature retinal expression of six6 is consistent with the observation that some patients with SIX6 mutations present with anophthalmia or microphthalmia, while others have normal size eyes, yet develop primary open angle glaucoma (POAG).…”

Section: Discussionsupporting

confidence: 86%

“…Six6 is expressed in the retina through all stages of eye development and its mutation results in diseases as distinct as anophthalmia and primary open angle glaucoma (Aijaz et al, 2005; Aldahmesh et al, 2013; Cheng et al, 2015; Elliott et al, 1993; Gallardo et al, 1999; Gallardo et al, 2004; Huai et al, 2011; Lemyre et al, 1998; Lumaka et al, 2012; López-Ríos et al, 1999; Nolen et al, 2006; Suda et al, 1999; Toy et al, 1998; Toy and Sundin, 1999; Yariz et al, 2015; Zuber et al, 1999) and reviewed in (Abu-Amero et al, 2015). How Six6 expression is controlled in the optic cup and mature retina has been extensively investigated in multiple species (Conte and Bovolenta, 2007; Larder et al, 2011; Tomarev, 1999; Viczian et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

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Distinct cis-acting regions control six6 expression during eye field and optic cup stages of eye formation

Ledford

Luna

Theisen

et al. 2017

Developmental Biology

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The eye field transcription factor, Six6, is essential for both the early (specification and proliferative growth) phase of eye formation, as well as for normal retinal progenitor cell differentiation. While genomic regions driving six6 optic cup expression have been described, the sequences controlling eye field and optic vesicle expression are unknown. Two evolutionary conserved regions 5′ and a third 3′ to the six6 coding region were identified, and together they faithfully replicate the endogenous X. laevis six6 expression pattern. Transgenic lines were generated and used to determine the onset and expression patterns controlled by the regulatory regions. The conserved 3′ region was necessary and sufficient for eye field and optic vesicle expression. In contrast, the two conserved enhancer regions located 5′ of the coding sequence were required together for normal optic cup and mature retinal expression. Gain-of-function experiments indicate endogenous six6 and GFP expression in F1 transgenic embryos are similarly regulated in response to candidate trans-acting factors. Importantly, CRISPR/CAS9-mediated deletion of the 3′ eye field/optic vesicle enhancer in X. laevis, resulted in a reduction in optic vesicle size. These results identify the cis-acting regions, demonstrate the modular nature of the elements controlling early versus late retinal expression, and identify potential regulators of six6 expression during the early stages of eye formation.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Distinct cis-acting regions control six6 expression during eye field and optic cup stages of eye formation

Ledford

Luna

Theisen

et al. 2017

Developmental Biology

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“…In 1991, Bennett et al was the first to suggest a relationship between the 14q22–q23 deletion and the presence of anophthalmia/microphthalmia (A/M) and pituitary malformations. This observation was followed by at least nine more reports of patients with A/M and other eye defects, and deletions of the 14q22–q23 region [Elliott et al, ; Lemyre et al, ; Nolen et al, ; Thienpont et al, ; Bakrania et al, ; Hayashi et al, ; Reis et al, ; Lumaka et al, ; Pearce et al, ]. These included an article that described four family members with the same deletion of 14q22.1–q22.2 and highly variable manifestations [Lumaka et al, ]; therefore, we present the second reported family carrying the same chromosomal deletion, and the first with a clinical diagnosis of a syndrome [Frías et al, ; Martínez‐Frías et al, ].…”

Section: Introductionmentioning

confidence: 99%

Haploinsufficiency of BMP4 gene may be the underlying cause of Frías syndrome

Martínez‐Fernández

Bermejo‐Sánchez

Fernández

et al. 2013

American J of Med Genetics Pt A

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In 2005, we reported on a family as having Frías syndrome (OMIM: 609640), with four affected members displaying a pattern of congenital defects nearly identical to those observed in a mother and son described by Frias [Frías et al. (1975). Birth Defects Orig Artic Ser 11:30-33]. These defects included growth deficiency, facial anomalies, and hand and foot alterations. We had the opportunity to study this family again due to the birth of another affected girl, who presented with similar facial characteristics to those of her elder half-sister and the rest of affected relatives, which consisted of mild exophthalmia, bilateral palpebral ptosis, downslanting palpebral fissures, and hypertelorism. We performed array-CGH, which identified an identical interstitial deletion of chromosome 14q22.1-q22.3 in the mother and two daughters. The deletion is 4.06 Mb in length and includes the BMP4 gene, a member of the bone morphogenetic protein (BMP) family of secreted proteins. A review of the literature showed that deletions or mutations of this gene underlie congenital defects affecting brain, eye, teeth, and digit development. Although the clinical manifestations of the current family correlate with the defects observed in patients having either 14q22-q23 deletions or mutations of BMP4, they show a milder phenotype. In order to understand the clinical variability, we evaluated the already known functional characteristics of the BMP gene members. This gene family plays an important role during early embryogenesis, and the complex synergistic functions and redundancies of the BMPs led us to conclude that haploinsufficiency of BMP4 is likely to be responsible for the clinical expression of Frías syndrome.

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“…Anophthalmia and other ocular anomalies were associated with heterozygous defects in OTX2 [3,8,9] or BMP4 [7,10,11], and also with deletions involving both these genes [4,6,12]. While OTX2 was deleted in all our patients, BMP4 was deleted only in Patient 1 (Figure 2).…”

Section: Discussionmentioning

confidence: 80%

Anophthalmia, hearing loss, abnormal pituitary development and response to growth hormone therapy in three children with microdeletions of 14q22q23

et al. 2014

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BackgroundMicrodeletions of 14q22q23 have been associated with eye abnormalities and pituitary defects. Other phenotypic features in deletion carriers including hearing loss and response to growth hormone therapy are less well recognized. We studied genotype and phenotype of three newly identified children with 14q22q23 deletions, two girls and one boy with bilateral anophthalmia, and compared them with previously published deletion patients and individuals with intragenic defects in genes residing in the region.ResultsThe three deletions were de novo and ranged in size between 5.8 and 8.9 Mb. All three children lacked one copy of the OTX2 gene and in one of them the deletion involved also the BMP4 gene. All three patients presented partial conductive hearing loss which tended to improve with age. Analysis of endocrine and growth phenotypes showed undetectable anterior pituitary, growth hormone deficiency and progressive growth retardation in all three patients. Growth hormone therapy led to partial catch-up growth in two of the three patients but just prevented further height loss in the third.ConclusionsThe pituitary hypoplasia, growth hormone deficiency and growth retardation associated with 14q22q23 microdeletions are very remarkable, and the latter appears to have an atypical response to growth hormone therapy in some of the cases.

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Variability in expression of a familial 2.79 Mb microdeletion in chromosome14q22.1–22.2

Cited by 18 publications

References 26 publications

Distinct cis-acting regions control six6 expression during eye field and optic cup stages of eye formation

Distinct cis-acting regions control six6 expression during eye field and optic cup stages of eye formation

Haploinsufficiency of BMP4 gene may be the underlying cause of Frías syndrome

Anophthalmia, hearing loss, abnormal pituitary development and response to growth hormone therapy in three children with microdeletions of 14q22q23

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