title: A-beta-subtype of ketosis-prone diabetes is not predominantly a monogenic diabetic syndrome.
abstract: OBJECTIVE
  Ketosis-prone diabetes (KPD) is an emerging syndrome that encompasses several distinct phenotypic subgroups that share a predisposition to diabetic ketoacidosis. We investigated whether the A-beta- subgroup of KPD, characterized by complete insulin dependence, absent beta-cell functional reserve, lack of islet cell autoantibodies, and strong family history of type 2 diabetes, represents a monogenic form of diabetes.
  
  
  METHODS
  Over 8 years, 37 patients with an A-beta- phenotype were identified in our longitudinally followed cohort of KPD patients. Seven genes, including hepatocyte nuclear factor 4A (HNF4A), glucokinase (GCK), HNF1A, pancreas duodenal homeobox 1 (PDX1), HNF1B, neurogenic differentiation 1 (NEUROD1), and PAX4, were directly sequenced in all patients. Selected gene regions were also sequenced in healthy, unrelated ethnically matched control subjects, consisting of 84 African American, 96 Caucasian, and 95 Hispanic subjects.
  
  
  RESULTS
  The majority (70%) of the A-beta- KPD patients had no significant causal polymorphisms in either the proximal promoter or coding regions of the seven genes. The combination of six potentially significant low-frequency, heterozygous sequence variants in HNF-1 alpha (A174V or G574S), PDX1 (putative 5'-untranslated region CCAAT box, P33T, or P239Q), or PAX4 (R133W) were found in 27% (10/37) of patients, with one additional patient revealing two variants, PDX1 P33T and PAX4 R133W. The A174V variant has not been previously reported.
  
  
  CONCLUSIONS
  Despite its well-circumscribed, robust, and distinctive phenotype of severe, nonautoimmune-mediated beta-cell dysfunction, A-beta- KPD is most likely not a predominantly monogenic diabetic syndrome. Several A-beta- KPD patients have low-frequency variants in HNF1A, PDX1, or PAX4 genes, which may be of functional significance in their pathophysiology.
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Wade C
authors.initials: WC
authors.lastname: Haaland
authors.forename: Diane I
authors.initials: DI
authors.lastname: Scaduto
authors.forename: Mario R
authors.initials: MR
authors.lastname: Maldonado
authors.forename: Dena L
authors.initials: DL
authors.lastname: Mansouri
authors.forename: Ramaswami
authors.initials: R
authors.lastname: Nalini
authors.forename: Dinakar
authors.initials: D
authors.lastname: Iyer
authors.forename: Sanjeet
authors.initials: S
authors.lastname: Patel
authors.forename: Anu
authors.initials: A
authors.lastname: Guthikonda
authors.forename: Christiane S
authors.initials: CS
authors.lastname: Hampe
authors.forename: Ashok
authors.initials: A
authors.lastname: Balasubramanyam
authors.forename: Michael L
authors.initials: ML
authors.lastname: Metzker
mesh_terms: D000328:Adult; D001323:Autoantibodies / Q000097:blood; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000145:classification / Q000188:drug therapy / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005941:Glucokinase / Q000235:genetics; D006442:Glycated Hemoglobin / Q000378:metabolism; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000627:therapeutic use; D050417:Insulin-Secreting Cells / Q000502:physiology; D007515:Islets of Langerhans / Q000276:immunology; D008297:Male; D008875:Middle Aged; D051761:Paired Box Transcription Factors / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics
chemical_list: D001323:Autoantibodies; D051792:Basic Helix-Loop-Helix Proteins; D005941:Glucokinase; D006442:Glycated Hemoglobin; D051539:Hepatocyte Nuclear Factor 1-beta; D051557:Hepatocyte Nuclear Factor 4; D018398:Homeodomain Proteins; D007328:Insulin; D051761:Paired Box Transcription Factors; D015534:Trans-Activators; C496495:HNF1B protein, human; C496592:HNF4A protein, human; C093970:NEUROD1 protein, human; C491709:PAX4 protein, human; C084010:pancreatic and duodenal homeobox 1 protein