Truncation of POC1A associated with short stature and extreme insulin resistance.
We describe a female proband with primordial dwarfism, skeletal dysplasia, facial dysmorphism, extreme dyslipidaemic insulin resistance and fatty liver associated with a novel homozygous frameshift mutation in POC1A, predicted to affect two of the three protein products of the gene. POC1A encodes a protein associated with centrioles throughout the cell cycle and implicated in both mitotic spindle and primary ciliary function. Three homozygous mutations affecting all isoforms of POC1A have recently been implicated in a similar syndrome of primordial dwarfism, although no detailed metabolic phenotypes were described. Primary cells from the proband we describe exhibited increased centrosome amplification and multipolar spindle formation during mitosis, but showed normal DNA content, arguing against mitotic skipping, cleavage failure or cell fusion. Despite evidence of increased DNA damage in cells with supernumerary centrosomes, no aneuploidy was detected. Extensive centrosome clustering both at mitotic spindles and in primary cilia mitigated the consequences of centrosome amplification, and primary ciliary formation was normal. Although further metabolic studies of patients with POC1A mutations are warranted, we suggest that POC1A may be added to ALMS1 and PCNT as examples of centrosomal or pericentriolar proteins whose dysfunction leads to extreme dyslipidaemic insulin resistance. Further investigation of links between these molecular defects and adipose tissue dysfunction is likely to yield insights into mechanisms of adipose tissue maintenance and regeneration that are critical to metabolic health.
The University of Cambridge Metabolic Research Laboratories Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK The National Institute for Health Research Cambridge Biomedical Research Centre Cambridge, UK Department of Pediatrics Sapienza University, Rome, Italy Metabolic Disease Group Wellcome Trust Sanger Institute, Cambridge, UK Wolfson Brain Imaging Centre University of Cambridge, Cambridge, UK National Institute for Health Research/Wellcome Trust Clinical Research Facility Cambridge, UK The University of Cambridge Metabolic Research Laboratories Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK The National Institute for Health Research Cambridge Biomedical Research Centre Cambridge, UK Department of Pediatrics Sapienza University, Rome, Italy Metabolic Disease Group Wellcome Trust Sanger Institute, Cambridge, UK Wolfson Brain Imaging Centre University of Cambridge, Cambridge, UK National Institute for Health Research/Wellcome Trust Clinical Research Facility Cambridge, UK.
Jian-Hua
JH
Chen
The University of Cambridge Metabolic Research Laboratories Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK The National Institute for Health Research Cambridge Biomedical Research Centre Cambridge, UK Department of Pediatrics Sapienza University, Rome, Italy Metabolic Disease Group Wellcome Trust Sanger Institute, Cambridge, UK Wolfson Brain Imaging Centre University of Cambridge, Cambridge, UK National Institute for Health Research/Wellcome Trust Clinical Research Facility Cambridge, UK.
Maria
M
Segni
The University of Cambridge Metabolic Research Laboratories Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK The National Institute for Health Research Cambridge Biomedical Research Centre Cambridge, UK Department of Pediatrics Sapienza University, Rome, Italy Metabolic Disease Group Wellcome Trust Sanger Institute, Cambridge, UK Wolfson Brain Imaging Centre University of Cambridge, Cambridge, UK National Institute for Health Research/Wellcome Trust Clinical Research Facility Cambridge, UK.
Felicity
F
Payne
The University of Cambridge Metabolic Research Laboratories Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK The National Institute for Health Research Cambridge Biomedical Research Centre Cambridge, UK Department of Pediatrics Sapienza University, Rome, Italy Metabolic Disease Group Wellcome Trust Sanger Institute, Cambridge, UK Wolfson Brain Imaging Centre University of Cambridge, Cambridge, UK National Institute for Health Research/Wellcome Trust Clinical Research Facility Cambridge, UK The University of Cambridge Metabolic Research Laboratories Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK The National Institute for Health Research Cambridge Biomedical Research Centre Cambridge, UK Department of Pediatrics Sapienza University, Rome, Italy Metabolic Disease Group Wellcome Trust Sanger Institute, Cambridge, UK Wolfson Brain Imaging Centre University of Cambridge, Cambridge, UK National Institute for Health Research/Wellcome Trust Clinical Research Facility Cambridge, UK.
Isabel
I
Huang-Doran
The University of Cambridge Metabolic Research Laboratories Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK The National Institute for Health Research Cambridge Biomedical Research Centre Cambridge, UK Department of Pediatrics Sapienza University, Rome, Italy Metabolic Disease Group Wellcome Trust Sanger Institute, Cambridge, UK Wolfson Brain Imaging Centre University of Cambridge, Cambridge, UK National Institute for Health Research/Wellcome Trust Clinical Research Facility Cambridge, UK The University of Cambridge Metabolic Research Laboratories Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK The National Institute for Health Research Cambridge Biomedical Research Centre Cambridge, UK Department of Pediatrics Sapienza University, Rome, Italy Metabolic Disease Group Wellcome Trust Sanger Institute, Cambridge, UK Wolfson Brain Imaging Centre University of Cambridge, Cambridge, UK National Institute for Health Research/Wellcome Trust Clinical Research Facility Cambridge, UK.
Alison
A
Sleigh
The University of Cambridge Metabolic Research Laboratories Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK The National Institute for Health Research Cambridge Biomedical Research Centre Cambridge, UK Department of Pediatrics Sapienza University, Rome, Italy Metabolic Disease Group Wellcome Trust Sanger Institute, Cambridge, UK Wolfson Brain Imaging Centre University of Cambridge, Cambridge, UK National Institute for Health Research/Wellcome Trust Clinical Research Facility Cambridge, UK The University of Cambridge Metabolic Research Laboratories Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK The National Institute for Health Research Cambridge Biomedical Research Centre Cambridge, UK Department of Pediatrics Sapienza University, Rome, Italy Metabolic Disease Group Wellcome Trust Sanger Institute, Cambridge, UK Wolfson Brain Imaging Centre University of Cambridge, Cambridge, UK National Institute for Health Research/Wellcome Trust Clinical Research Facility Cambridge, UK.
Claire
C
Adams
The University of Cambridge Metabolic Research Laboratories Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK The National Institute for Health Research Cambridge Biomedical Research Centre Cambridge, UK Department of Pediatrics Sapienza University, Rome, Italy Metabolic Disease Group Wellcome Trust Sanger Institute, Cambridge, UK Wolfson Brain Imaging Centre University of Cambridge, Cambridge, UK National Institute for Health Research/Wellcome Trust Clinical Research Facility Cambridge, UK The University of Cambridge Metabolic Research Laboratories Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK The National Institute for Health Research Cambridge Biomedical Research Centre Cambridge, UK Department of Pediatrics Sapienza University, Rome, Italy Metabolic Disease Group Wellcome Trust Sanger Institute, Cambridge, UK Wolfson Brain Imaging Centre University of Cambridge, Cambridge, UK National Institute for Health Research/Wellcome Trust Clinical Research Facility Cambridge, UK.
David B
DB
Savage
The University of Cambridge Metabolic Research Laboratories Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK The National Institute for Health Research Cambridge Biomedical Research Centre Cambridge, UK Department of Pediatrics Sapienza University, Rome, Italy Metabolic Disease Group Wellcome Trust Sanger Institute, Cambridge, UK Wolfson Brain Imaging Centre University of Cambridge, Cambridge, UK National Institute for Health Research/Wellcome Trust Clinical Research Facility Cambridge, UK The University of Cambridge Metabolic Research Laboratories Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK The National Institute for Health Research Cambridge Biomedical Research Centre Cambridge, UK Department of Pediatrics Sapienza University, Rome, Italy Metabolic Disease Group Wellcome Trust Sanger Institute, Cambridge, UK Wolfson Brain Imaging Centre University of Cambridge, Cambridge, UK National Institute for Health Research/Wellcome Trust Clinical Research Facility Cambridge, UK.
Stephen
S
O'Rahilly
The University of Cambridge Metabolic Research Laboratories Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK The National Institute for Health Research Cambridge Biomedical Research Centre Cambridge, UK Department of Pediatrics Sapienza University, Rome, Italy Metabolic Disease Group Wellcome Trust Sanger Institute, Cambridge, UK Wolfson Brain Imaging Centre University of Cambridge, Cambridge, UK National Institute for Health Research/Wellcome Trust Clinical Research Facility Cambridge, UK The University of Cambridge Metabolic Research Laboratories Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK The National Institute for Health Research Cambridge Biomedical Research Centre Cambridge, UK Department of Pediatrics Sapienza University, Rome, Italy Metabolic Disease Group Wellcome Trust Sanger Institute, Cambridge, UK Wolfson Brain Imaging Centre University of Cambridge, Cambridge, UK National Institute for Health Research/Wellcome Trust Clinical Research Facility Cambridge, UK rks16@cam.ac.uk ib1@sanger.ac.uk.
Robert K
RK
Semple
The University of Cambridge Metabolic Research Laboratories Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK The National Institute for Health Research Cambridge Biomedical Research Centre Cambridge, UK Department of Pediatrics Sapienza University, Rome, Italy Metabolic Disease Group Wellcome Trust Sanger Institute, Cambridge, UK Wolfson Brain Imaging Centre University of Cambridge, Cambridge, UK National Institute for Health Research/Wellcome Trust Clinical Research Facility Cambridge, UK The University of Cambridge Metabolic Research Laboratories Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK The National Institute for Health Research Cambridge Biomedical Research Centre Cambridge, UK Department of Pediatrics Sapienza University, Rome, Italy Metabolic Disease Group Wellcome Trust Sanger Institute, Cambridge, UK Wolfson Brain Imaging Centre University of Cambridge, Cambridge, UK National Institute for Health Research/Wellcome Trust Clinical Research Facility Cambridge, UK The University of Cambridge Metabolic Research Laboratories Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK The National Institute for Health Research Cambridge Biomedical Research Centre Cambridge, UK Department of Pediatrics Sapienza University, Rome, Italy Metabolic Disease Group Wellcome Trust Sanger Institute, Cambridge, UK Wolfson Brain Imaging Centre University of Cambridge, Cambridge, UK National Institute for Health Research/Wellcome Trust Clinical Research Facility Cambridge, UK rks16@cam.ac.uk ib1@sanger.ac.uk.
Inês
I
Barroso
D000328:Adult; D000595:Amino Acid Sequence; D001827:Body Height / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D002502:Centrioles / Q000235:genetics*; D018385:Centrosome / Q000502:physiology; D003598:Cytoskeletal Proteins; D004392:Dwarfism / Q000235:genetics*; D019066:Facies; D005234:Fatty Liver / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008938:Mitosis / Q000235:genetics; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D016415:Sequence Alignment; D008941:Spindle Apparatus / Q000502:physiology
D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; C575745:POC1A protein, human; D020033:Protein Isoforms; D011506:Proteins
POC1A; centriole; centrosome; diabetes; dyslipidaemia; insulin resistance; primary cilium; short stature; skeletal dysplasia