title: Partial and whole gene deletion mutations of the GCK and HNF1A genes in maturity-onset diabetes of the young.
abstract: OBJECTIVE
  Heterozygous mutations of glucokinase (GCK) and hepatocyte nuclear factor-1 alpha (HNF1A; also known as hepatic transcription factor 1 [TCF1]) genes are the most common cause of MODY. Genomic deletions of the HNF1B (also known as TCF2) gene have recently been shown to account for one third of mutations causing renal cysts and diabetes syndrome. We investigated the prevalence of partial and whole gene deletions in UK patients meeting clinical criteria for GCK or HNF-1alpha/-4alpha MODY and in whom no mutation had been identified by sequence analysis.
  
  
  METHODS
  A multiplex ligation-dependent probe amplification (MLPA) assay was developed using synthetic oligonucleotide probes for 30 exons of the GCK, HNF1A and HNF4A genes.
  
  
  RESULTS
  Partial or whole gene deletions were identified in 1/29 (3.5%) probands using the GCK MLPA assay and 4/60 (6.7%) of probands using the HNF1A/-4A MLPA assay. Four different deletions were detected: GCK exon 2, HNF1A exon 1, HNF1A exons 2 to 10 and HNF1A exons 1 to 10. An additional Danish pedigree with evidence of linkage to HNF1A had a deletion of exons 2 to 10. Testing other family members confirmed co-segregation of the deletion mutations with diabetes in the pedigrees.
  
  
  CONCLUSIONS
  Large deletions encompassing whole exons can cause GCK or HNF-1alpha MODY and will not be detected by sequencing. Gene dosage assays, such as MLPA, are a useful adjunct to sequence analysis when a diagnosis of MODY is strongly suspected.
authors.affiliation: Institute of Biomedical Science and Clinical Medicine, Peninsula Medical School, Exeter, UK. Sian.Ellard@rdeft.nhs.uk
authors.forename: S
authors.initials: S
authors.lastname: Ellard
authors.forename: K
authors.initials: K
authors.lastname: Thomas
authors.forename: E L
authors.initials: EL
authors.lastname: Edghill
authors.forename: M
authors.initials: M
authors.lastname: Owens
authors.forename: L
authors.initials: L
authors.lastname: Ambye
authors.forename: J
authors.initials: J
authors.lastname: Cropper
authors.forename: J
authors.initials: J
authors.lastname: Little
authors.forename: M
authors.initials: M
authors.lastname: Strachan
authors.forename: A
authors.initials: A
authors.lastname: Stride
authors.forename: B
authors.initials: B
authors.lastname: Ersoy
authors.forename: H
authors.initials: H
authors.lastname: Eiberg
authors.forename: O
authors.initials: O
authors.lastname: Pedersen
authors.forename: M H
authors.initials: MH
authors.lastname: Shepherd
authors.forename: T
authors.initials: T
authors.lastname: Hansen
authors.forename: L W
authors.initials: LW
authors.lastname: Harries
authors.forename: A T
authors.initials: AT
authors.lastname: Hattersley
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002675:Child, Preschool; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D005941:Glucokinase / Q000172:deficiency / Q000235:genetics*; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000172:deficiency / Q000235:genetics*; D006801:Humans; D008297:Male; D010375:Pedigree; D010641:Phenotype