Anauxetic dysplasia, a spondylometaepiphyseal dysplasia with extreme dwarfism

Horn, Denise; Rupprecht, E; Kunze, Jürgen; Spranger, J.

doi:10.1136/jmg.38.4.262

Cited by 23 publications

(25 citation statements)

References 11 publications

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“…In this study we report the mapping of mutations causing a severe bone dysplasia in a family of unrelated unaffected parents with two affected siblings. The clinical and radiographic features of the affected siblings showed similarities to anauxetic dysplasia, an autosomal recessive spondylo-epi-metaphyseal dysplasia characterized by extremely short stature [8], [9]. Both siblings had severe growth retardation of prenatal onset, a bone dysplasia affecting the epiphyses and metaphyses of the long bones particularly in the lower limbs, and abnormalities of the spine including irregularly shaped vertebral bodies and marked cervical spine instability (Figure 1).…”

Section: Introductionmentioning

confidence: 97%

Whole-Exome Re-Sequencing in a Family Quartet Identifies POP1 Mutations As the Cause of a Novel Skeletal Dysplasia

et al. 2011

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Recent advances in DNA sequencing have enabled mapping of genes for monogenic traits in families with small pedigrees and even in unrelated cases. We report the identification of disease-causing mutations in a rare, severe, skeletal dysplasia, studying a family of two healthy unrelated parents and two affected children using whole-exome sequencing. The two affected daughters have clinical and radiographic features suggestive of anauxetic dysplasia (OMIM 607095), a rare form of dwarfism caused by mutations of RMRP. However, mutations of RMRP were excluded in this family by direct sequencing. Our studies identified two novel compound heterozygous loss-of-function mutations in POP1, which encodes a core component of the RNase mitochondrial RNA processing (RNase MRP) complex that directly interacts with the RMRP RNA domains that are affected in anauxetic dysplasia. We demonstrate that these mutations impair the integrity and activity of this complex and that they impair cell proliferation, providing likely molecular and cellular mechanisms by which POP1 mutations cause this severe skeletal dysplasia.

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Section: Introductionmentioning

confidence: 97%

Whole-Exome Re-Sequencing in a Family Quartet Identifies POP1 Mutations As the Cause of a Novel Skeletal Dysplasia

et al. 2011

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“…The RMRP mutations in Anauxetic dysplasia (MIM 607095) disrupt its endonucleolytic activity, specifically leading to poor processing of rRNA while allowing for normal mRNA processing of B-cyclin [116]. This disorder is characterized by midface hypoplasia and extreme short stature with defects in the growth plate including marked hypocellularity of the resting cartilage, severely reduce numbers of proliferating chondrocytes, and diminished columnization of the hypertrophic zone [119,120]. …”

Section: Introductionmentioning

confidence: 99%

Ribosome biogenesis in skeletal development and the pathogenesis of skeletal disorders

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Merrill

2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The skeleton affords a framework and structural support for vertebrates, while also facilitating movement, protecting vital organs, and providing a reservoir of minerals and cells for immune system and vascular homeostasis. The mechanical and biological functions of the skeleton are inextricably linked to the size and shape of individual bones, the diversity of which is dependent in part upon differential growth and proliferation. Perturbation of bone development, growth and proliferation, can result in congenital skeletal anomalies, which affect approximately 1 in 3000 live births [1]. Ribosome biogenesis is integral to all cell growth and proliferation through its roles in translating mRNAs and building proteins. Disruption of any steps in the process of ribosome biogenesis can lead to congenital disorders termed ribosomopathies. In this review, we discuss the role of ribosome biogenesis in skeletal development and in the pathogenesis of congenital skeletal anomalies.

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“…The first and fifth metacarpals are short and wide with small, late-ossifying epiphyses and bullet-shaped middle phalanges. A large reduction in the number of chondrocytes in the resting and proliferating zones, with diminished columnization of the hypertrophic zone has also been observed (18,21,22).…”

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confidence: 99%

Broadening the phenotypic spectrum of POP1‐skeletal dysplasias: identification of POP1 mutations in a mild and severe skeletal dysplasia

et al. 2017

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Processing of Precursor 1 (POP1) is a large protein common to the ribonuclease‐mitochondrial RNA processing (RNase‐MRP) and RNase‐P (RMRP) endoribonucleoprotein complexes. Although its precise function is unknown, it appears to participate in the assembly or stability of both complexes. Numerous RMRP mutations have been reported in individuals with cartilage‐hair hypoplasia (CHH) but, to date, only three POP1 mutations have been described in two families with features similar to anauxetic dysplasia (AD). We present two further individuals, one with severe short stature and a relatively mild skeletal dysplasia and another in whom AD was suspected. Biallelic POP1 mutations were identified in both. A missense mutation and a novel single base deletion were detected in proband 1, p.[Pro582Ser]:[Glu870fs*5]. Markedly reduced abundance of RMRP and elevated levels of pre5.8s rRNA was observed. In proband 2, a homozygous novel POP1 mutation was identified, p.[(Asp511Tyr)];[(Asp511Tyr)]. These two individuals show the phenotypic extremes in the clinical presentation of POP1‐dysplasias. Although CHH and other skeletal dysplasias caused by mutations in RMRP or POP1 are commonly cited as ribosomal biogenesis disorders, recent studies question this assumption. We discuss the past and present knowledge about the function of the RMRP complex in skeletal development.

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Anauxetic dysplasia, a spondylometaepiphyseal dysplasia with extreme dwarfism

Cited by 23 publications

References 11 publications

Whole-Exome Re-Sequencing in a Family Quartet Identifies POP1 Mutations As the Cause of a Novel Skeletal Dysplasia

Whole-Exome Re-Sequencing in a Family Quartet Identifies POP1 Mutations As the Cause of a Novel Skeletal Dysplasia

Ribosome biogenesis in skeletal development and the pathogenesis of skeletal disorders

Broadening the phenotypic spectrum of POP1‐skeletal dysplasias: identification of POP1 mutations in a mild and severe skeletal dysplasia

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