Low density lipoprotein receptor-related protein 5 (LRP5) mutations and osteoporosis, impaired glucose metabolism and hypercholesterolaemia.
OBJECTIVE
Mutations in the low-density lipoprotein receptor-related protein 5 gene (LRP5) underlie osteoporosis-pseudoglioma syndrome. Animal models implicate a role for LRP5 in lipid and glucose homeostasis. The objective was to evaluate metabolic consequences of LRP5 mutations in humans.


METHODS
Thirteen Finnish individuals with homozygous or heterozygous LRP5 mutations were assessed for bone health, glucose and lipid metabolism, and for serum serotonin concentration. Results were compared with findings in family members without mutations.


METHODS
Bone mineral density (BMD), vertebral morphology, oral and intravenous glucose tolerance tests, lipid profile and serum serotonin concentrations.


RESULTS
Two individuals were homozygous for R570W, one compound heterozygous for R570W and R1036Q, and 10 were heterozygous (six for R570W, three for R1036Q and one for R925C). Subjects with two LRP5 mutations had multiple spinal fractures and low BMD. Subjects with one mutation had significantly lower median lumbar spine (P = 0.004) and femoral neck (P = 0.005) BMD Z-scores, and more often vertebral fractures than the 18 individuals without mutations. Of the 12 subjects with LRP5 mutation six had diabetes and one had impaired glucose tolerance. Intravenous glucose tolerance tests suggested impaired beta-cell function; no insulin resistance was observed. Prevalence of hypercholesterolaemia was similar in mutation positive and negative subjects. Serum serotonin concentrations showed a trend towards higher concentrations in subjects with LRP5 mutation.


CONCLUSIONS
We found high prevalence of osteoporosis and abnormal glucose metabolism in subjects with LRP5 mutation(s). Further studies are needed to establish the role of LRP5 in glucose and lipid metabolism.
Saarinen
Anne
A
Folkhälsan Institute of Genetics, University of Helsinki, Helsinki, Finland.
Saukkonen
Tero
T
Kivelä
Tero
T
Lahtinen
Ulla
U
Laine
Christine
C
Somer
Mirja
M
Toiviainen-Salo
Sanna
S
Cole
William G
WG
Lehesjoki
Anna-Elina
AE
Mäkitie
Outi
O
D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D015519:Bone Density / Q000235:genetics; D005260:Female; D005272:Femur Neck / Q000378:metabolism; D005910:Glioma / Q000235:genetics; D018149:Glucose Intolerance / Q000235:genetics; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics*; D026502:LDL-Receptor Related Proteins / Q000235:genetics*; D050356:Lipid Metabolism; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008159:Lumbar Vertebrae / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010024:Osteoporosis / Q000235:genetics*; D013577:Syndrome
D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5