Dataset Information

Absence of mutations in NR2E1 and SNX3 in five patients with MMEP (microcephaly, microphthalmia, ectrodactyly, and prognathism) and related phenotypes.

ABSTRACT: BACKGROUND: A disruption of sorting nexin 3 (SNX3) on 6q21 was previously reported in a patient with MMEP (microcephaly, microphthalmia, ectrodactyly, and prognathism) and t(6;13)(q21;q12) but no SNX3 mutations were identified in another sporadic case of MMEP, suggesting involvement of another gene. In this work, SNX3 was sequenced in three patients not previously studied for this gene. In addition, we test the hypothesis that mutations in the neighbouring gene NR2E1 may underlie MMEP and related phenotypes. METHODS: Mutation screening was performed in five patients: the t(6;13)(q21;q12) MMEP patient, three additional patients with possible MMEP or a related phenotype, and one patient with oligodactyly, ulnar aplasia, and a t(6;7)(q21;q31.2) translocation. We used sequencing to exclude SNX3 coding mutations in three patients not previously studied for this gene. To test the hypothesis that mutations in NR2E1 may contribute to MMEP or related phenotypes, we sequenced the entire coding region, complete 5' and 3' untranslated regions, consensus splice-sites, and evolutionarily conserved regions including core and proximal promoter in all five patients. Two-hundred and fifty control subjects were genotyped for any candidate mutation. RESULTS: We did not detect any synonymous nor nonsynonymous coding mutations of NR2E1 or SNX3. In one patient with possible MMEP, we identified a candidate regulatory mutation that has been reported previously in a patient with microcephaly but was not found in 250 control subjects examined here. CONCLUSION: Our results do not support involvement of coding mutations in NR2E1 or SNX3 in MMEP or related phenotypes; however, we cannot exclude the possibility that regulatory NR2E1 or SNX3 mutations or deletions at this locus may underlie abnormal human cortical development in some patients.

SUBMITTER: Kumar RA

PROVIDER: S-EPMC1950490 | biostudies-literature | 2007

REPOSITORIES: biostudies-literature

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Absence of mutations in NR2E1 and SNX3 in five patients with MMEP (microcephaly, microphthalmia, ectrodactyly, and prognathism) and related phenotypes.

Kumar Ravinesh A RA Everman David B DB Morgan Chad T CT Slavotinek Anne A Schwartz Charles E CE Simpson Elizabeth M EM

BMC medical genetics 20070726

<h4>Background</h4>A disruption of sorting nexin 3 (SNX3) on 6q21 was previously reported in a patient with MMEP (microcephaly, microphthalmia, ectrodactyly, and prognathism) and t(6;13)(q21;q12) but no SNX3 mutations were identified in another sporadic case of MMEP, suggesting involvement of another gene. In this work, SNX3 was sequenced in three patients not previously studied for this gene. In addition, we test the hypothesis that mutations in the neighbouring gene NR2E1 may underlie MMEP and ...[more]

PMID: 17655765

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Project description:PURPOSE: Nuclear receptor 2E1 (NR2E1) is a transcription factor with many roles during eye development and thus may be responsible for the occurrence of certain congenital eye disorders in humans. To test this hypothesis, we screened NR2E1 for candidate mutations in patients with aniridia and other congenital ocular malformations (anterior segment dysgenesis, congenital optic nerve malformation, and microphthalmia). METHODS: The NR2E1 coding region, 5' and 3' untranslated regions (UTRs), exon flanking regions including consensus splice sites, and six evolutionarily conserved non-coding candidate regulatory regions were analyzed by sequencing 58 probands with aniridia of whom 42 were negative for PAX6 mutations. Nineteen probands with anterior segment dysgenesis, one proband with optic nerve malformation, and two probands with microphthalmia were also sequenced. The control population comprised 376 healthy individuals. All sequences were analyzed against the GenBank sequence AL078596.8 for NR2E1. In addition, the coding region and flanking intronic sequences of FOXE3, FOXC1, PITX2, CYP1B1, PAX6, and B3GALTL were sequenced in one patient and his relatives. RESULTS: Sequencing analysis showed 17 NR2E1 variants including two novel rare non-coding variants (g.-1507G>A, g.14258C>T), and one novel rare coding variant (p.Arg274Gly). The latter was present in a male diagnosed with Peters' anomaly who subsequently was found to have a known causative mutation for Peters' plus syndrome in B3GALTL (c.660+1G>A). In addition, the NR2E1 novel rare variant Arg274Gly was present in the unaffected mother of the patient but absent in 746 control chromosomes. CONCLUSIONS: We eliminated a major role for NR2E1 regulatory and coding mutations in aniridia and found a novel rare coding variant in NR2E1. In addition, we found no coding region variation in the control population for NR2E1, which further supports its previously reported high level of conservation and low genetic diversity. Future NR2E1 studies in ocular disease groups such as those involving retinal and optic nerve abnormalities should be undertaken to determine whether NR2E1 plays a role in these conditions.

Dataset Information

Absence of mutations in NR2E1 and SNX3 in five patients with MMEP (microcephaly, microphthalmia, ectrodactyly, and prognathism) and related phenotypes.

Publications

Absence of mutations in NR2E1 and SNX3 in five patients with MMEP (microcephaly, microphthalmia, ectrodactyly, and prognathism) and related phenotypes.

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