title: Novel missense mutation in the RSPO4 gene in congenital hyponychia and evidence for a polymorphic initiation codon (p.M1I).
abstract: BACKGROUND
  Anonychia/hyponychia congenita is a rare autosomal recessive developmental disorder characterized by the absence (anonychia) or hypoplasia (hyponuchia) of finger- and/or toenails frequently caused by mutations in the R-spondin 4 (RSPO4) gene.
  
  
  METHODS
  Three hypo/anonychia consanguineous Pakistani families were ascertained and genotyped using microsatellite markers spanning the RSPO4 locus on chromosome 20p13. Mutation screening of the RSPO4 gene was carried out by direct sequencing of the entire coding region and all intron-exon boundaries.
  
  
  RESULTS
  Mutations in the RSPO4 gene were identified in all families including a novel missense mutation c.178C>T (p.R60W) and two recurrent variants c.353G>A (p.C118Y) and c.3G>A (p.M1I). The c.3G>A variant was identified in unaffected family members and a control sample in a homozygous state.
  
  
  CONCLUSIONS
  This study raises to 17 the number of known RSPO4 mutations and further expands the molecular repertoire causing hypo/anonychia. The c.353G>A emerges as a recurrent change with a possible founder effect in the Pakistani population. Our findings suggest that c.3G>A is not sufficient to cause the disorder and could be considered a polymorphism.
authors.affiliation: Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad 38000, Pakistan.
authors.forename: Tahir Naeem
authors.initials: TN
authors.lastname: Khan
authors.forename: Joakim
authors.initials: J
authors.lastname: Klar
authors.forename: Sadia
authors.initials: S
authors.lastname: Nawaz
authors.forename: Muhammad
authors.initials: M
authors.lastname: Jameel
authors.forename: Muhammad
authors.initials: M
authors.lastname: Tariq
authors.forename: Naveed Altaf
authors.initials: NA
authors.lastname: Malik
authors.forename: Shahid M
authors.initials: SM
authors.lastname: Baig
authors.forename: Niklas
authors.initials: N
authors.lastname: Dahl
mesh_terms: D016022:Case-Control Studies; D002890:Chromosomes, Human, Pair 20; D018387:Codon, Initiator; D003241:Consanguinity; D018703:Founder Effect; D006720:Homozygote; D006801:Humans; D020125:Mutation, Missense; D009264:Nails, Malformed / Q000151:congenital* / Q000235:genetics; D010154:Pakistan; D010375:Pedigree; D019699:Thrombospondins / Q000235:genetics*; D000098907:R-Spondins
chemical_list: D018387:Codon, Initiator; D019699:Thrombospondins; C516169:RSPO4 protein, human; D000098907:R-Spondins