Deletion and Point Mutations of PTHLH Cause Brachydactyly Type E

被引:100
作者
Klopocki, Eva [1 ,10 ]
Hennig, Bianca P. [1 ]
Dathe, Katarina [1 ]
Koll, Randi [1 ]
de Ravel, Thomy [2 ]
Baten, Emiel [3 ]
Blom, Eveline [4 ]
Gillerot, Yves [5 ]
Weigel, Johannes F. W. [6 ]
Krueger, Gabriele [7 ]
Hiort, Olaf [8 ]
Seemann, Petra [9 ]
Mundlos, Stefan [1 ,9 ,10 ]
机构
[1] Charite, Inst Med Genet, D-13353 Berlin, Germany
[2] Katholieke Univ Leuven Hosp, Ctr Human Genet, B-3000 Louvain, Belgium
[3] AZ St Lucas, B-8310 Brugge, Belgium
[4] Maastricht Univ Ctr, Dept Clin Genet, NL-6200 Maastricht, Netherlands
[5] Clin Univ St Luc, Ctr Genet Humaine, B-1200 Brussels, Belgium
[6] Univ Childrens Hosp, D-04103 Leipzig, Germany
[7] Univ Klinikum Rostock, Abt Med Genet, D-18057 Rostock, Germany
[8] Med Univ Lubeck, Dept Pediat, D-23538 Lubeck, Germany
[9] Berlin Brandenburg Ctr Regenerat Therapies BCRT, D-13353 Berlin, Germany
[10] Max Planck Inst Mol Genet, D-14195 Berlin, Germany
关键词
HORMONE-RELATED PEPTIDE; ENDOCHONDRAL BONE-FORMATION; MESSENGER-RNA SURVEILLANCE; PARATHYROID-HORMONE; INDIAN HEDGEHOG; HEREDITARY OSTEODYSTROPHY; PTH/PTHRP RECEPTOR; GROWTH-PLATE; PROTEIN; DIFFERENTIATION;
D O I
10.1016/j.ajhg.2010.01.023
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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 BIDE, short stature, and learning disabilities, we detected a microdeletion of similar to 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.
引用
收藏
页码:434 / 439
页数:6
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