A Novel Autosomal Recessive, Progeroid Syndrome with Short Stature, Mandibular Hypoplasia, Osteoporosis and Short Eyebrows Due to a Homozygous Mutation in PRRT3

CONTEXT: Despite considerable progress in elucidating the molecular basis of various progeroid syndromes, some rare patients remain unexplained. OBJECTIVE: To elucidate molecular genetic basis of a novel autosomal recessive progeroid syndrome. PARTICIPANTS: A 21-year-old male and his 17-year-old sister with short stature, mandibular hypoplasia, pointed nose, shrill voice, severe osteoporosis, and short eyebrows; and their unaffected siblings and parents belonging to a consanguineous Arab family. RESULTS: Using exome and Sanger sequencing, we report a novel homozygous p.Glu394Lys disease-causing mutation in proline rich transmembrane protein 3 (PRRT3). PRRT3 belongs to the family of proline-rich proteins containing several repeats of a short proline-rich sequence but its function remains to be determined. Preliminary observations showing co-localization of Prrt3 and synaptophysin support its role in vesicle exocytosis. Consistent with the highest mRNA expression of PRRT3 in the pituitary, both the patients had mild growth hormone deficiency but had near normal reproductive development. CONCLUSIONS: We conclude that the homozygous p.Glu394Lys mutation in PRRT3 causes a novel autosomal recessive, progeroid syndrome with short stature, mandibular hypoplasia, osteoporosis, short eyebrows and mild GH deficiency. Our findings extend the spectrum of progeroid syndromes and elucidate important functions of PRRT3 in human biology including secretion of growth hormone from the pituitary.