Isolated Pancreatic Aplasia Due to a Hypomorphic PTF1A Mutation.
Homozygous truncating mutations in the helix-loop-helix transcription factor PTF1A are a rare cause of pancreatic and cerebellar agenesis. The correlation of Ptf1a dosage with pancreatic phenotype in a mouse model suggested the possibility of finding hypomorphic PTF1A mutations in patients with pancreatic agenesis or neonatal diabetes but no cerebellar phenotype. Genome-wide single nucleotide polymorphism typing in two siblings with neonatal diabetes from a consanguineous pedigree revealed a large shared homozygous region (31 Mb) spanning PTF1A Sanger sequencing of PTF1A identified a novel missense mutation, p.P191T. Testing of 259 additional patients using a targeted next-generation sequencing assay for 23 neonatal diabetes genes detected one additional proband and an affected sibling with the same homozygous mutation. All four patients were diagnosed with diabetes at birth and were treated with insulin. Two of the four patients had exocrine pancreatic insufficiency requiring replacement therapy but none of the affected individuals had neurodevelopmental delay. Transient transfection assays of the mutant protein demonstrated a 75% reduction in transactivation activity. This study shows that the functional severity of a homozygous mutation impacts the severity of clinical features found in patients.
Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, U.K.
Jayne A L
JA
Houghton
Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, TX.
Galvin H
GH
Swift
Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, U.K.
Charles
C
Shaw-Smith
Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, U.K.
Sarah E
SE
Flanagan
Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, U.K.
Elisa
E
de Franco
Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, U.K.
Richard
R
Caswell
Department of Endocrinology, Great Ormond Street Hospital for Children, London, U.K.
Khalid
K
Hussain
Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
Sarar
S
Mohamed
Department of Paediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.
Majedah
M
Abdulrasoul
Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, U.K. a.t.hattersley@exeter.ac.uk raymond.macdonald@utsouthwestern.edu.
Andrew T
AT
Hattersley
Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, TX a.t.hattersley@exeter.ac.uk raymond.macdonald@utsouthwestern.edu.
Raymond J
RJ
MacDonald
Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, U.K.
Sian
S
Ellard
D002648:Child; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D020125:Mutation, Missense; D010179:Pancreas / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
D014157:Transcription Factors; C062602:transcription factor PTF1