title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child & Family Research Institute, Department of Medical Genetics, University of British Columbia, 950 West 28th Ave, Vancouver, V5Z 4H4, Canada. rakumar@cmmt.ubc.ca
authors.forename: Ravinesh A
authors.initials: RA
authors.lastname: Kumar
authors.forename: David B
authors.initials: DB
authors.lastname: Everman
authors.forename: Chad T
authors.initials: CT
authors.lastname: Morgan
authors.forename: Anne
authors.initials: A
authors.lastname: Slavotinek
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schwartz
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Simpson
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000328:Adult; D002648:Child; D002896:Chromosomes, Human, Pair 6; D003062:Codon; D004480:Ectromelia / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008831:Microcephaly / Q000235:genetics; D008850:Microphthalmos / Q000235:genetics; D009154:Mutation; D057093:Orphan Nuclear Receptors; D010641:Phenotype; D011378:Prognathism / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid; D017422:Sequence Analysis, DNA; D058305:Sorting Nexins; D013577:Syndrome; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: D003062:Codon; C088601:NR2E1 protein, human; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; C513980:SNX3 protein, human; D058305:Sorting Nexins; D033921:Vesicular Transport Proteins