title: Deletion and point mutations of PTHLH cause brachydactyly type E.
abstract: Autosomal-dominant brachydactyly type E (BDE) is a congenital limb malformation characterized by small hands and feet predominantly as a result of shortened metacarpals and metatarsals. In a large pedigree with BDE, short stature, and learning disabilities, we detected a microdeletion of approximately 900 kb encompassing PTHLH, the gene coding for parathyroid hormone related protein (PTHRP). PTHRP is known to regulate the balance between chondrocyte proliferation and the onset of hypertrophic differentiation during endochondral bone development. Inactivation of Pthrp in mice results in short-limbed dwarfism because of premature differentiation of chondrocyte. On the basis of our initial finding, we tested further individuals with BDE and short stature for mutations in PTHLH. We identified two missense (L44P and L60P), a nonstop (X178WextX( *)54), and a nonsense (K120X) mutation. The missense mutation L60P was tested in chicken micromass culture with the replication-competent avian sarcoma leukosis virus retroviral expression system and was shown to result in a loss of function. Thus, loss-of-function mutations in PTHLH cause BDE with short stature.
authors.affiliation: Institut für Medizinische Genetik, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Klopocki
authors.forename: Bianca P
authors.initials: BP
authors.lastname: Hennig
authors.forename: Katarina
authors.initials: K
authors.lastname: Dathe
authors.forename: Randi
authors.initials: R
authors.lastname: Koll
authors.forename: Thomy
authors.initials: T
authors.lastname: de Ravel
authors.forename: Emiel
authors.initials: E
authors.lastname: Baten
authors.forename: Eveline
authors.initials: E
authors.lastname: Blom
authors.forename: Yves
authors.initials: Y
authors.lastname: Gillerot
authors.forename: Johannes F W
authors.initials: JF
authors.lastname: Weigel
authors.forename: Gabriele
authors.initials: G
authors.lastname: Krüger
authors.forename: Olaf
authors.initials: O
authors.lastname: Hiort
authors.forename: Petra
authors.initials: P
authors.lastname: Seemann
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D018389:Codon, Nonsense; D004195:Disease Models, Animal; D005260:Female; D005532:Foot Deformities, Congenital / Q000235:genetics / Q000473:pathology; D005799:Genes, Dominant; D006130:Growth Disorders / Q000235:genetics / Q000473:pathology; D006228:Hand Deformities, Congenital / Q000235:genetics / Q000473:pathology; D006801:Humans; D017880:Limb Deformities, Congenital / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D020125:Mutation, Missense; D044162:Parathyroid Hormone-Related Protein / Q000172:deficiency / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion
chemical_list: D018389:Codon, Nonsense; C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D011994:Recombinant Proteins