PAX6 missense variants in two families with isolated foveal hypoplasia and nystagmus: evidence of paternal postzygotic mosaicism

Abstract PAX6 is considered the master regulator of eye development, the majority of variants affecting this gene cause the pan-ocular developmental eye disorder aniridia. Although no genotype-phenotype correlations are clearly established, missense variants affecting the DNA-binding paired domain of PAX6 are usually associated with non-aniridia phenotypes like microphthalmia, coloboma or isolated foveal hypoplasia. In this study, we report two missense heterozygous variants in the paired domain of PAX6 resulting in isolated foveal hypoplasia with nystagmus in two independent families: c.112 C > G; p.(Arg38Gly) and c.214 G > C; p.(Gly72Arg) in exons 5 and 6, respectively. Furthermore, we provide evidence that paternal postzygotic mosaicism is the cause of inheritance, with clinically unaffected fathers and reduced affected allele fraction. This work contributes to increase the phenotypic spectrum caused by PAX6 variants, and to our knowledge, is the first report to describe the presence of postzygotic parental mosaicism causing isolated foveal hypoplasia with nystagmus. These results support the growing evidence that suggest an overestimation of sporadic cases with PAX6 variants, which has strong implications for both genetic counselling and family planning.

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Helix 2 of the paired domain plays a key role in the regulation of DNA-binding by the Pax-3 homeodomain

Nucleic Acids Research ◽

10.1093/nar/26.20.4574 ◽

1998 ◽

Vol 26 (20) ◽

pp. 4574-4581 ◽

Cited By ~ 20

Author(s):

A. S. Fortin ◽

D. A. Underhill ◽

P. Gros

Keyword(s):

Dna Binding ◽

Paired Domain

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A novel nuclear localization signal spans the linker of the two DNA-binding subdomains in the conserved paired domain of Pax6

Genes & Genetic Systems ◽

10.1266/ggs.17-00057 ◽

2018 ◽

Vol 93 (2) ◽

pp. 75-81 ◽

Cited By ~ 4

Author(s):

Hiromasa Tabata ◽

Akihiro Koinui ◽

Atsushi Ogura ◽

Daisuke Nishihara ◽

Hiroaki Yamamoto

Keyword(s):

Dna Binding ◽

Nuclear Localization ◽

Nuclear Localization Signal ◽

Paired Domain ◽

Localization Signal

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In vivo requirement for the paired domain and homeodomain of the paired segmentation gene product

Development ◽

10.1242/dev.122.9.2673 ◽

1996 ◽

Vol 122 (9) ◽

pp. 2673-2685 ◽

Cited By ~ 8

Author(s):

C. Bertuccioli ◽

L. Fasano ◽

S. Jun ◽

S. Wang ◽

G. Sheng ◽

...

Keyword(s):

Dna Binding ◽

Binding Mode ◽

Cooperative Interaction ◽

Paired Domain ◽

Conserved Motifs ◽

Dna Binding Domains ◽

Binding Domains ◽

Segment Polarity ◽

Functionally Impaired

The Drosophila pair-rule gene paired is required for the correct expression of the segment polarity genes wingless, engrailed and gooseberry. It encodes a protein containing three conserved motifs: a homeodomain (HD), a paired domain (PD) and a PRD (His/Pro) repeat. We use a rescue assay in which paired (or a mutated version of paired in which the functions of the conserved motifs have been altered) is expressed under the control of its own promoter, in the absence of endogenous paired, to dissect the Paired protein in vivo. We show that both the HD and the N- terminal subdomain of the PD (PAI domain) are absolutely required within the same molecule for normal paired function. In contrast, the conserved C-terminal subdomain of the PD (RED domain) appears to be dispensable. Furthermore, although a mutation abolishing the ability of the homeodomain to dimerize results in an impaired Paired molecule, this molecule is nonetheless able to mediate a high degree of rescue. Finally, a paired transgene lacking the PRD repeat is functionally impaired, but still able to rescue to viability. We conclude that, while Prd can use its DNA-binding domains combinatorially in order to achieve different DNA-binding specificities, its principal binding mode requires a cooperative interaction between the PAI domain and the homeodomain.

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Characterization of quail Pax-6 (Pax-QNR) proteins expressed in the neuroretina.

Molecular and Cellular Biology ◽

10.1128/mcb.13.12.7257 ◽

1993 ◽

Vol 13 (12) ◽

pp. 7257-7266 ◽

Cited By ~ 64

Author(s):

C Carriere ◽

S Plaza ◽

P Martin ◽

B Quatannens ◽

M Bailly ◽

...

Keyword(s):

Dna Binding ◽

Autosomal Dominant ◽

Paired Domain ◽

Terminal Part ◽

Dominant Mutation ◽

Dna Binding Domains ◽

Binding Domains ◽

Carboxyl Terminal

After differential screening of a cDNA library constructed from quail neuroretina cells (QNR) infected with the v-myc-containing avian retrovirus MC29, we have isolated a cDNA clone, Pax-QNR, homologous to the murine Pax-6, which is mutated in the autosomal dominant mutation small eye of mice and in the disorder aniridia in humans. Here we report the characterization of the Pax-QNR proteins expressed in the avian neuroretina. From bacterially expressed Pax-QNR peptides, we obtained rabbit antisera directed against different domains of the protein: paired domain (serum 11), domain between the paired domain and homeodomain (serum 12), homeodomain (serum 13), and carboxyl-terminal part (serum 14). Sera 12, 13, and 14 were able to specifically recognize five proteins (48, 46, 43, 33, and 32 kDa) in the neuroretina. In contrast to proteins of 48, 46, and 43 kDa, proteins of 33 and 32 kDa were not recognized by the paired antiserum (serum 11). Paired-less and paired-containing proteins exhibited the same half-life (6 h) and were phosphorylated mostly on serine residues. Immunoprecipitations performed with subcellular fractions of neuroretinas showed that the paired-containing proteins were located in the nucleus, whereas the 33- and 32-kDa proteins were found essentially in the cytoplasmic compartment. However, immunofluorescence experiments performed after transient transfections showed that p46 and p33/32 were also located in vivo into the nucleus. Thus, the Pax-QNR/Pax-6 gene can produce proteins with two DNA-binding domains as well as proteins containing only the DNA-binding homeodomain.

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