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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Available from: Olaf Hiort, Oct 04, 2015
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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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    ABSTRACT: Brachydactyly (BD) refers to the shortening of the hands, feet or both. There are different types of BD; among them, type E (BDE) is a rare type that can present as an isolated feature or as part of more complex syndromes, such as: pseudohypoparathyroidism (PHP), hypertension with BD or Bilginturan BD (HTNB), BD with mental retardation (BDMR) or BDE with short stature, PTHLH type. Each syndrome has characteristic patterns of skeletal involvement. However, brachydactyly is not a constant feature and shows a high degree of phenotypic variability. In addition, there are other syndromes that can be misdiagnosed as brachydactyly type E; some of which will also be discussed. The objective of this review is to describe some of the syndromes in which BDE is present, focusing on clinical, biochemical and genetic characteristics as features of differential diagnoses, with the aim of establishing an algorithm for their differential diagnosis. As in our experience, many of these patients are recruited at Endocrinology and/or Pediatric Endocrinology Services due to their short stature, we have focused the algorithm in those steps that could mainly help these professionals.
    Orphanet Journal of Rare Diseases 09/2013; 8(1):141. DOI:10.1186/1750-1172-8-141 · 3.36 Impact Factor
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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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    ABSTRACT: The so-called "enchondromatoses" are skeletal disorders defined by the presence of ectopic cartilaginous tissue within bone tissue. The clinical and radiographic features of the different enchondromatoses are distinct, and grouping them does not reflect a common pathogenesis but simply a similar radiographic appearance and thus the need for a differential diagnosis. Recent advances in the understanding of their molecular and cellular bases confirm the heterogeneous nature of the different enchondromatoses. Some, like Ollier disease, Maffucci disease, metaphyseal chondromatosis with hydroxyglutaric aciduria, and metachondromatosis are produced by a dysregulation of chondrocyte proliferation, while others (such as spondyloenchondrodysplasia or dysspondyloenchondromatosis) are caused by defects in structure or metabolism of cartilage or bone matrix. In other forms (e.g., the dominantly inherited genochondromatoses), the basic defect remains to be determined. The classification, proposed by Spranger and associates in 1978 and tentatively revised twice, was based on the radiographic appearance, the anatomic sites involved, and the mode of inheritance. The new classification proposed here integrates the molecular genetic advances and delineates phenotypic families based on the molecular defects. Reference radiographs are provided to help in the diagnosis of the well-defined forms. In spite of advances, many cases remain difficult to diagnose and classify, implying that more variants remain to be defined at both the clinical and molecular levels.
    American Journal of Medical Genetics Part C Seminars in Medical Genetics 08/2012; 160C(3):154-64. DOI:10.1002/ajmg.c.31331 · 3.91 Impact Factor
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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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    ABSTRACT: SOX5 encodes a transcription factor involved in the regulation of chondrogenesis and the development of the nervous system. Despite its important developmental roles, SOX5 disruption has yet to be associated with human disease. We report one individual with a reciprocal translocation breakpoint within SOX5, eight individuals with intragenic SOX5 deletions (four are apparently de novo and one inherited from an affected parent), and seven individuals with larger 12p12 deletions encompassing SOX5. Common features in these subjects include prominent speech delay, intellectual disability, behavior abnormalities, and dysmorphic features. The phenotypic impact of the deletions may depend on the location of the deletion and, consequently, which of the three major SOX5 protein isoforms are affected. One intragenic deletion, involving only untranslated exons, was present in a more mildly affected subject, was inherited from a healthy parent and grandparent, and is similar to a deletion found in a control cohort. Therefore, some intragenic SOX5 deletions may have minimal phenotypic effect. Based on the location of the deletions in the subjects compared to the controls, the de novo nature of most of these deletions, and the phenotypic similarities among cases, SOX5 appears to be a dosage-sensitive, developmentally important gene.
    Human Mutation 01/2012; 33(4):728-40. DOI:10.1002/humu.22037 · 5.14 Impact Factor
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