Schimke immuno-osseous dysplasia: A newly recognized multisystem disease

Spranger, Jürgen W.; Hinkel, G. K.; Stöß, H; Thoenes, W.; Wargowski, David S.; Zepp, Fred

doi:10.1016/s0022-3476(05)81040-6

Cited by 113 publications

(127 citation statements)

References 18 publications

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“…ized by autosomal recessive inheritance, spondyloepiphyseal dysplasia causing growth retardation, defective cellular immunity, progressive nephropathy leading to renal failure, hyperpigmented macules, and dysmorphic facial features (1)(2)(3)(4). Half of SIOD patients also have hypothyroidism, half episodic cerebral ischemia, and a tenth bone marrow failure.…”

Section: S Chimke Immuno-osseous Dysplasia (Siod) Is Character-mentioning

confidence: 99%

Schimke Immuno-Osseous Dysplasia: Expression of SMARCAL1 in Blood and Kidney Provides Novel Insight Into Disease Phenotype

et al. 2008

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Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive disorder caused by loss-of-function mutations in SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1), with clinical features of growth retardation, spondylo-epiphyseal dysplasia, nephrotic syndrome, and immunodeficiency. We report a patient with SIOD and SMARCAL1 splice mutation (IVS4-2 AϾG) in a nonconsanguineous Ashkenazi family, who came to our attention at 1 mo of age due to renal malformation and only later developed signs compatible with Schimke. Interestingly, residual SMARCAL1 mRNA levels in the patient's peripheral blood were lower compared with those observed in both asymptomatic brothers' carrying the same bi-allelic mutation, whereas the latter had levels similar to those found in heterozygous carriers (parents and sister). Examination of the carrier frequency of the splice mutation in the Ashkenazi population demonstrated 1 carrier in 760 DNA samples. In situ localization of SMARCAL1 in human kidneys as well as analysis of its temporal expression during murine nephrogenesis and in the metanephric organ culture suggested a role in the early renal progenitor population and after renal maturation. Thus, disease severity within the same family might be modified by the splicing machinery. The renal expression pattern of SMARCAL1 explains a broader spectrum of renal disease in SIOD than previously described. (Pediatr Res 63: 398-403, 2008) S chimke immuno-osseous dysplasia (SIOD) is characterized by autosomal recessive inheritance, spondyloepiphyseal dysplasia causing growth retardation, defective cellular immunity, progressive nephropathy leading to renal failure, hyperpigmented macules, and dysmorphic facial features (1-4). Half of SIOD patients also have hypothyroidism, half episodic cerebral ischemia, and a tenth bone marrow failure.SIOD is caused by mutations in SWI/SNF2 related, matrix associated, actin dependent regulator of chromatin, subfamily a-like 1(SMARCAL1) (5). SNF2 related proteins participate in the DNA nucleosome restructuring which commonly occurs during gene regulation and DNA replication, recombination, methylation, and repair (6,7).Recent analysis of detailed autopsies to correlate clinical and pathologic findings in SIOD identified T cell deficiency in peripheral lymphoid organs, defective chondrogenesis, focal segmental glomerulosclerosis (FSGS), cerebral ischemic lesions, and premature atherosclerosis (8).Herein, we report on a male patient, 6 y old, who came to our attention after birth due to renal malformation and later on developed growth retardation, bone dysplasia, and steroidresistant nephrotic syndrome and was shown to harbor a bi-allelic SMARCAL1 splice mutation. Investigation of his nonconsanguineous Ashkenazi family lead us to discover phenotypic diversity and variable expressivity of SMARCAL1 in the family along with low carrier frequency of the splice mutation in the Ashkenazi population. In addition, in situ localization of SMARCAL1 in the...

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Section: S Chimke Immuno-osseous Dysplasia (Siod) Is Character-mentioning

confidence: 99%

Schimke Immuno-Osseous Dysplasia: Expression of SMARCAL1 in Blood and Kidney Provides Novel Insight Into Disease Phenotype

et al. 2008

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“…HARP (HepA-related protein), also known as SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), is a member of the SWI/SNF family of proteins (Eisen et al 1995;Coleman et al 2000;Flaus et al 2006). Mutations in HARP are responsible for an autosomal recessive disorder known as Schimke immunoosseous dysplasia (SIOD), with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction, and T-cell immunodeficiency (Schimke et al 1971;Spranger et al 1991;Boerkoel et al 2000). Recent studies suggested that HARP has an unusual biochemical activity as an annealing helicase, which is opposite to helicases that are normally involved in DNA unwinding (Yusufzai and Kadonaga 2008).…”

mentioning

confidence: 99%

“…Mutations in HARP are responsible for an autosomal recessive disorder known as Schimke immunoosseous dysplasia (SIOD), with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction, and T-cell immunodeficiency (Schimke et al 1971;Spranger et al 1991;Boerkoel et al 2000). Recent studies suggested that HARP has an unusual biochemical activity as an annealing helicase, which is opposite to helicases that are normally involved in DNA unwinding (Yusufzai and Kadonaga 2008).…”

mentioning

confidence: 99%

The annealing helicase HARP protects stalled replication forks

Yuan¹,

Ghosal²,

Chen³

2009

Genes Dev.

135

171

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Mutations in HepA-related protein (HARP) are the only identified causes of Schimke immunoosseous dysplasia (SIOD). HARP has a unique annealing helicase activity in vitro, but the in vivo functional significance remains unknown. Here, we demonstrated that HARP is recruited to stalled replication forks via its direct interaction with Replication protein A (RPA). Cells with HARP depletion displayed increased spontaneous DNA damage and G2/M arrest, suggesting that HARP normally acts to stabilize stalled replication forks. Our data place the annealing helicase activity of HARP at replication forks and propose that SIOD syndrome may be caused by the destabilization of replication forks during cell proliferation. HARP (HepA-related protein), also known as SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), is a member of the SWI/SNF family of proteins (Eisen et al. 1995;Coleman et al. 2000;Flaus et al. 2006). Mutations in HARP are responsible for an autosomal recessive disorder known as Schimke immunoosseous dysplasia (SIOD), with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction, and T-cell immunodeficiency (Schimke et al. 1971;Spranger et al. 1991;Boerkoel et al. 2000). Recent studies suggested that HARP has an unusual biochemical activity as an annealing helicase, which is opposite to helicases that are normally involved in DNA unwinding (Yusufzai and Kadonaga 2008). However, the exact biological function of this HARP annealing helicase activity remains unknown.In this study, we report that HARP associates with Replication protein A (RPA) in vitro and in vivo. RPA was initially identified as an ssDNA-binding protein that is absolutely required for DNA replication of simian virus 40 (SV40) (for reviews, see Waga and Stillman 1998;Stenlund 2003;Fanning et al. 2006). Human RPA is a stable heterotrimer composed of three subunits-RPA70, RPA32, and RPA14 (also named as RPA1, RPA2, and RPA3)-that are conserved among eukaryotes. RPA is essential for DNA replication, repair, and recombination, and DNA damage signaling pathways in eukaryotic cells (Zou and Elledge 2003;Binz et al. 2004;Stauffer and Chazin 2004b;Fanning et al. 2006). The functions of RPA in these diverse processes depend on its ssDNA-binding activity and its ability to interact with multiple proteins involved in these pathways (for reviews, see Fanning et al. 2006;Zou et al. 2006). Therefore, RPA can be considered as an adaptor protein that facilitates various biochemical reactions that occur at or involve ssDNA. The interaction between HARP and RPA suggest that HARP may function during replication and/or DNA repair. Indeed, our subsequent studies indicate that HARP is involved in the protection of stalled replication forks and thus provide a plausible mechanism for the development of SIOD syndrome. Results and DiscussionIn an effort to identify new RPA-associated proteins, we performed tandem affinity purification (TAP) using soluble or chromatin fraction prepared from 293T cells ...

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“…The past sixty years of hematopoietic biology research has increased our understanding of marrow stromal cell types, as well as the three-dimensional regions that provide structure and organization of cell signaling for the maintenance and propagation of HSPCs. The study of the hematopoietic niche will continue to provide details on necessary niche components, which may assist in the understanding of other stem cell niches, including the vascular, skin, hair, and neural niches, and provide therapeutic cues for immuno-osseous diseases that present with skeletal defects and altered hematopoiesis, such as McKusick type metaphyseal chondrodysplasia (cartilage-hair hypoplasia; CHH), Shwachmen-Diamond syndrome, Schimke dysplasia (Spranger et al 1991;Kuijpers et al 2004;Hermanns et al 2005), and others. …”

Section: Summary and Perspectivesmentioning

confidence: 99%

“…This relationship also extends to an interdependence between bone and hematopoiesis during immune cell development, however the critical cell types and extracellular matrix components involved in establishing and maintaining hematopoietic niches within the bone marrow are only recently beginning to be defined. Indeed, some immuno-osseous disorders with hematopoietic defects such as bone marrow failure and immune dysfunction, as well as certain cancers, may result from a defective hematopoietic niche (Spranger et al 1991;Kuijpers et al 2004;Hermanns et al 2005;Raaijmakers et al 2010). Likewise during aging, a progressive decline in cell replacement and repair manifests in both the skeletal and hematopoietic systems with reduced bone mass and diminished blood cell formation respectively (as reviewed in (Rossi et al 2008) and (Gruver et al 2007).…”

Section: Introductionmentioning

confidence: 99%