De novo 2q36.1q36.3 interstitial deletion involving the <i>PAX3</i> and <i>EPHA4</i> genes in a fetus with spina bifida and cleft palate

Goumy, Carole; Gay‐Bellile, Mathilde; Eymard-Pierre, Éléonore; Kemeny, Stéphan; Gouas, Laëtitia; Déchelotte, P.; Gallot, Denis; Véronèse, Lauren; Tchirkov, Andréï; Pebrel‐Richard, Céline; Vago, Philippe

doi:10.1002/bdra.23246

Cited by 13 publications

(8 citation statements)

References 22 publications

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“…Targeted homozygous disruption of EphA4 results in viable and fertile mice that exhibit defects in the corticospinal tract and hindlimb innervation as well as defects of the coronal suture (Dottori et al, ; Helmbacher et al, ; Ting et al, ). Of interest though, a recent report of a fetus with cleft palate and spina bifida that harbored a deletion of the genomic region including the EPHA4 and PAX3 genes suggested that EphA4 might be involved in palate development (Goumy et al, ). We, therefore, asked whether EphA3 might be redundant with EphA4 in the development of the secondary palate.…”

Section: Resultsmentioning

confidence: 99%

Embryonic expression of EphA receptor genes in mice supports their candidacy for involvement in cleft lip and palate

Agrawal

Wang

Kim

et al. 2014

Developmental Dynamics

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Background Eph receptors, comprising the A- and B- subfamilies, are the largest family of receptor tyrosine kinases in the mammalian genome, and their function is critical for morphogenesis in a variety of contexts. Whereas signaling through B-type Ephs has been demonstrated to play a role in cleft lip and palate (CL/P), the involvement of A-type Ephs has not been examined in this context notwithstanding a recent genome-wide association study that identified the EPHA3 locus as a candidate for non-syndromic CL/P. Results Here we present a systematic analysis of the gene expression patterns for the nine EphA receptors at progressive stages of mouse development and find that EphA3, EphA4 and EphA7 exhibit restricted overlapping patterns of expression during palate development. We find that homozygous mutation of EphA3 or compound homozygous mutation of EphA3 and EphA4 in mice does not result in defective midfacial development, supporting the possibility of redundant function with EphA7. We also document previously undescribed expression patterns in other tissues of the craniofacial complex including the lacrimal duct and salivary glands. Conclusions Together, these results are consistent with the hypothesis that mutations in EPHA family genes may cause CL/P and also suggest that functional redundancy between family members may be at play.

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Section: Resultsmentioning

confidence: 99%

Embryonic expression of EphA receptor genes in mice supports their candidacy for involvement in cleft lip and palate

Agrawal

Wang

Kim

et al. 2014

Developmental Dynamics

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“…The scenario in humans is somewhat similar in that there are 4 studies to date demonstrating the involvement of haploinsufficiency in the causation of spina bifida. The Pax3 gene and the EphA4 gene act in concert with each other in causing spina bifida due to interstitial deletion at position 2q36 [ 318 ]. Furthermore, in the same paper, Goumy et al [ 318 ] suggested that a similar phenomenon occurs in the mouse when taking into account the spina bifida phenotype seen on the Splotch mouse that is affected by both Pax3 [ 93 ] and EphA4 [ 319 ], albeit the link between the two in the mouse has yet to be ascertained.…”

Section: Haploinsufficiency In Mouse and Manmentioning

confidence: 99%

“…The Pax3 gene and the EphA4 gene act in concert with each other in causing spina bifida due to interstitial deletion at position 2q36 [ 318 ]. Furthermore, in the same paper, Goumy et al [ 318 ] suggested that a similar phenomenon occurs in the mouse when taking into account the spina bifida phenotype seen on the Splotch mouse that is affected by both Pax3 [ 93 ] and EphA4 [ 319 ], albeit the link between the two in the mouse has yet to be ascertained. The hedgehog pathway has also been implicated in humans, where spina bifida occurs when Patched is perturbed when implicated with Gorlin syndrome [ 320 ].…”

Section: Haploinsufficiency In Mouse and Manmentioning

confidence: 99%

Spina Bifida: Pathogenesis, Mechanisms, and Genes in Mice and Humans

et al. 2017

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Spina bifida is among the phenotypes of the larger condition known as neural tube defects (NTDs). It is the most common central nervous system malformation compatible with life and the second leading cause of birth defects after congenital heart defects. In this review paper, we define spina bifida and discuss the phenotypes seen in humans as described by both surgeons and embryologists in order to compare and ultimately contrast it to the leading animal model, the mouse. Our understanding of spina bifida is currently limited to the observations we make in mouse models, which reflect complete or targeted knockouts of genes, which perturb the whole gene(s) without taking into account the issue of haploinsufficiency, which is most prominent in the human spina bifida condition. We thus conclude that the need to study spina bifida in all its forms, both aperta and occulta, is more indicative of the spina bifida in surviving humans and that the measure of deterioration arising from caudal neural tube defects, more commonly known as spina bifida, must be determined by the level of the lesion both in mouse and in man.

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“…It has been suggested that PAX3 haploinsufficiency may be associated with neural tube defects in humans but the precise mechanism is not elucidated while it is better characterized in animal models. 18,19 Among PAX3 heterozygotes often a specific variant is responsible for a very similar phenotype in particular concerning the presence or absence of limb involvement. In one of the families, the condition caused by a pathogenic variant in the paired domain of PAX3 p.Asn47Lys was first reported as a distinct syndrome of craniofacial, hand anomalies, and sensorineural deafness with very similar features in the mother and affected children.…”

Section: Discussionmentioning

confidence: 99%

Biallelic variants in PAX3 cause Klein syndrome

Salah

Meiner

Abumayaleh³

et al. 2022

Clinical Genetics

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Waardenburg syndrome is a group of genetic conditions that can cause hearing loss and pigmentation deficiency of the hair, skin, and eyes. Klein-Waardenburg syndrome (Waardenburg syndrome type 3) represents a distinct presentation of Waardenburg syndrome type 1 and includes musculoskeletal abnormalities in addition to dystopia canthorum hearing loss and pigmentary changes. Heterozygous or homozygous variants in the PAX3 gene cause Klein-Waardenburg syndrome. Here we report on a new severely affected child, with a homozygous PAX3 variant (c.251C>T; p.Ser84Phe), review the features of the syndrome, and propose a new classification. The designation of Waardenburg syndrome should be given only to patients with monoallelic pathogenic variants in PAX3 whether or not musculoskeletal abnormalities are present. Patients with biallelic PAX3 variants should be outlined as a distinct group and designated Klein syndrome.

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De novo 2q36.1q36.3 interstitial deletion involving the PAX3 and EPHA4 genes in a fetus with spina bifida and cleft palate

Cited by 13 publications

References 22 publications

Embryonic expression of EphA receptor genes in mice supports their candidacy for involvement in cleft lip and palate

Embryonic expression of EphA receptor genes in mice supports their candidacy for involvement in cleft lip and palate

Spina Bifida: Pathogenesis, Mechanisms, and Genes in Mice and Humans

Biallelic variants in PAX3 cause Klein syndrome

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