Deletion and Point Mutations of PTHLH Cause Brachydactyly Type E

Institut für Medizinische Genetik, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.
The American Journal of Human Genetics (Impact Factor: 10.93). 02/2010; 86(3):434-9. DOI: 10.1016/j.ajhg.2010.01.023
Source: PubMed


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.

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    • "Apart from BDE, other features were seen in these patients (Additional file 1: Table S6): most but not all had short stature [76,82], tooth problems were reported by Klopocki et al. in two out of five families [82], and those affected with translocation t(8;12) had dysmorphic facies with macrocephaly [76]. Neither hypertension nor mental retardation was mentioned, but learning difficulties were reported in one family [82]. "
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    • "02 , and see Table I ] did not reveal abnormalities , but CGH array revealed heterozygosity for a microduplication that contained twelve genes including the gene for PTHLH , a PTH - like protein that binds to the PTH receptor . Deletion of and loss of function mutations in the PTHLH gene have been implicated in the etiol - ogy of brachydactyly E [ Klopocki et al . , 2010 ; Maass et al . , 2010 ] . This Figure 5 . Genochondromatosis . A – C : The index child , who was clinically asymptomatic , was ascertained when he sustained a distal femoral fracture ( see arrow ) . Radiographs showed extensive enchondromatous lesions at the metaphyses of the long bones with extension into the diaphyses . Note that the"
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    • "Behavior problems have only been described in one 13-month-old male with poor psychosocial contact (Orye and Craen, 1975), although a majority of these cases were identified through traditional cytogenetic techniques, and the inclusion of SOX5 in the deleted intervals is uncertain. The brachydactyly observed in these individuals is type E, with shortening of the metacarpals and metatarsals, and, along with the short stature and oligodontia seen in some of these individuals, may be due to the deletion of PTHLH within 12p11.22 (Klopocki et al., 2010). "
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