Deletion and Point Mutations of PTHLH Cause Brachydactyly Type E

Eva Klopocki, Bianca P. Hennig, Katarina Dathe, Randi Koll, Thomy de Ravel, Emiel Baten, Eveline Blom, Yves Gillerot, Johannes F.W. Weigel, Gabriele Krüger, Olaf Hiort, Petra Seemann, Stefan Mundlos*

*Corresponding author for this work
95 Citations (Scopus)


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 ∼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.

Original languageEnglish
JournalAmerican Journal of Human Genetics
Issue number3
Pages (from-to)434-439
Number of pages6
Publication statusPublished - 2010

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)


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