Manifestations and treatment of Schimke immuno-osseous dysplasia: 14 new cases and a review of the literature

Boerkoel, Cornelius F.; O’Neill, Sinéad M; André, J. L.; Benke, Paul J.; Bogdanović, Radovan; Bulla, M; Burguet, A.; Cockfield, Sandra M.; Cordeiro, Isabel; Ehrich, J. H. H.; Fründ, Stefan; Geary, D. F.; Ieshima, Atsushi; Illies, Friederike; Joseph, Mark; Kaitila, Ilkka; Lama, Giuliana; Leheup, B.; Ludman, Mark D.; McLeod, David; Medeira, Ana; Milford, David V.; Örmälä, Timo; Rener-Primec, Zvonka; Santavá, A; Santos, Heloísa G. dos; Schmidt, Beate; Smith, Graham C.; Spranger, Jürgen W.; Župančič, N.; Weksberg, Rosanna

doi:10.1007/s004310050001

Cited by 157 publications

(238 citation statements)

References 18 publications

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“…SIOD symptoms commonly include skeletal dysplasia, T-cell immunodeficiency, and kidney failure (Boerkoel et al 2000). At the cellular level, SMARCAL1 deficiency causes increased DNA replication-associated damage (Bansbach et al , 2010Postow et al 2009;Yuan et al 2009) and sensitizes cells to DNA-damaging agents that inhibit DNA replication Ciccia et al 2009;Yuan et al 2009).…”

mentioning

confidence: 99%

SMARCAL1 catalyzes fork regression and Holliday junction migration to maintain genome stability during DNA replication

Bétous¹,

Mason²,

Rambo³

et al. 2012

Genes Dev.

251

307

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SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A-like1) maintains genome integrity during DNA replication. Here we investigated its mechanism of action. We found that SMARCAL1 travels with elongating replication forks, and its absence leads to MUS81-dependent double-strand break formation. Binding to specific nucleic acid substrates activates SMARCAL1 activity in a reaction that requires its HARP2 (Hep-A-related protein 2) domain. Homology modeling indicates that the HARP domain is similar in structure to the DNA-binding domain of the PUR proteins. Limited proteolysis, small-angle X-ray scattering, and functional assays indicate that the core enzymatic unit consists of the HARP2 and ATPase domains that fold into a stable structure. Surprisingly, SMARCAL1 is capable of binding three-way and four-way Holliday junctions and model replication forks that lack a designed ssDNA region. Furthermore, SMARCAL1 remodels these DNA substrates by promoting branch migration and fork regression. SMARCAL1 mutations that cause Schimke immunoosseous dysplasia or that inactivate the HARP2 domain abrogate these activities. These results suggest that SMARCAL1 continuously surveys replication forks for damage. If damage is present, it remodels the fork to promote repair and restart. Failures in the process lead to activation of an alternative repair mechanism that depends on MUS81-catalyzed cleavage of the damaged fork.

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mentioning

confidence: 99%

SMARCAL1 catalyzes fork regression and Holliday junction migration to maintain genome stability during DNA replication

Bétous¹,

Mason²,

Rambo³

et al. 2012

Genes Dev.

251

307

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“…These biological differences might explain why we were unable to detect a molecular phenotype in the mice. The cultured primary dermal fibroblasts of SIOD patients also did not exhibit dysregulated elastogenesis, which we hypothesize is secondary to cell type-related differences since not all tissues are equally affected in SIOD; for example, patients do not have any pronounced skin manifestations, other than hyperpigmented macules (11).…”

Section: Discussionmentioning

confidence: 81%

“…Key manifestations of the disease include growth failure due to spondyloepiphyseal dysplasia, renal failure due to focal segmental glomerulosclerosis, T-cell immunodeficiency, facial dysmorphism, and hyperpigmented macules (9). Approximately 50% of SIOD patients also develop vascular disease (10), and the vascular complications are refractory to treatment and a common cause of death (11).…”

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confidence: 99%

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Transcriptional and posttranscriptional mechanisms contribute to the dysregulation of elastogenesis in Schimke immuno-osseous dysplasia

Morimoto

Wang

et al. 2015

Pediatr Res

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BACKGROUND: Schimke immuno-osseous dysplasia (SIOD)is an autosomal recessive disorder caused by mutations in SMARCAL1. A frequent complication is arteriosclerosis associated with reduced elastin expression; however, the mechanism underlying the reduced elastin expression remains unknown. METHODS: Expression of transcriptional regulators of elastin (ELN) and microRNA (miRNA) regulators of ELN messenger RNA (mRNA), ELN promoter methylation, and ELN mRNA poly(A) tail length were assessed by quantitative RT-PCR, bisulfite Sanger sequencing, and the Poly(A) Tail Length Assay Kit, respectively, in unaffected developing human aortae and in an SIOD aorta. RESULTS: Comparing unaffected fetal and adult aortae, ELN precursor mRNA (pre-mRNA) levels remained nearly constant, whereas mRNA levels declined by ~10 2 -fold. This corresponded with a reduction in poly(A) tail length but not with changes in the other parameters. In contrast, compared to the unaffected fetal aortae, the SIOD aorta had 18-fold less ELN pre-mRNA and 10 4 -fold less mRNA. This corresponded with increased expression of miRNA regulators and shorter ELN mRNA poly(A) tail lengths but not with altered expression of ELN transcriptional regulators or ELN promoter methylation. CONCLUSION: Posttranscriptional mechanisms account for the reduction in ELN mRNA levels in unaffected aortae, whereas transcriptional and posttranscriptional mechanisms reduce elastin expression in SIOD aorta and predispose to arteriosclerosis.S chimke immuno-osseous dysplasia (SIOD, OMIM 242900) is a rare autosomal recessive multisystemic disorder caused by mutations in the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) gene (1). SMARCAL1 functions as a DNA-dependent annealing helicase (2) that recognizes single-stranded to double-stranded DNA transitions and binds to transcriptionally active chromatin (3). SMARCAL1 is involved in the DNA stress response (4,5), the reactivation of stalled replication forks (6)(7)(8), and the modulation of gene expression (3). Key manifestations of the disease include growth failure due to spondyloepiphyseal dysplasia, renal failure due to focal segmental glomerulosclerosis, T-cell immunodeficiency, facial dysmorphism, and hyperpigmented macules (9). Approximately 50% of SIOD patients also develop vascular disease (10), and the vascular complications are refractory to treatment and a common cause of death (11).The vascular disease in SIOD manifests as migraine-like headaches, transient ischemic attacks, and cerebrovascular accidents (11). The arterial histopathology shows intimal and medial hyperplasia, smooth muscle cell hyperplasia, and fragmented and disorganized elastin fibers (10,12). Molecular studies suggest reduced elastogenesis (10); however, the mechanism underlying this remains unknown.Elastin, which is critical for the development and maintenance of the arteries (13,14), confers the elastic recoil properties required for the proper function of the arteries as well as other load-bearing...

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“…2,5,7 Life expectancy of severely affected individuals with SIOD typically does not exceed 1 decade, as these patients usually succumb to renal failure or infection. 3 In this paper we report a pediatric case of internal carotid artery (ICA) stenosis secondary to SIOD treated by carotid arteriotomy and patching. To our knowledge this represents the first reported case of carotid patching and revascularization in a pediatric patient.…”

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confidence: 99%

Internal carotid artery surgical revascularization in a pediatric patient with Schimke immuno-osseous dysplasia

Westbroek¹,

Mukerji²,

Kalanithi³

2015

PED

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Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive disorder characterized by spondyloepiphyseal dysplasia, episodic lymphopenia, renal failure, and cerebrovascular disease secondary to arteriosclerosis and myointimal hyperplasia. In this paper the authors report the first known application of internal carotid artery (ICA) surgical revascularization to relieve a high-grade focal stenosis of the ICA in a pediatric patient, a 6-year-old boy with SIOD. The clinical presentation, imaging features, operative technique, and postoperative course are described and the molecular genetics, pathophysiology, and treatment considerations in SIOD are discussed.

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Manifestations and treatment of Schimke immuno-osseous dysplasia: 14 new cases and a review of the literature

Abstract: Schimke immuno-osseous dysplasia is a multi-system autosomal recessive disorder with variable expression that affects the skeletal, renal, immune, vascular, and haematopoietic systems. Medical therapy is limited especially for more severely affected individuals.

Cited by 157 publications

References 18 publications

SMARCAL1 catalyzes fork regression and Holliday junction migration to maintain genome stability during DNA replication

SMARCAL1 catalyzes fork regression and Holliday junction migration to maintain genome stability during DNA replication

Transcriptional and posttranscriptional mechanisms contribute to the dysregulation of elastogenesis in Schimke immuno-osseous dysplasia

Internal carotid artery surgical revascularization in a pediatric patient with Schimke immuno-osseous dysplasia

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