Neurologic Phenotype of Schimke Immuno-Osseous Dysplasia and Neurodevelopmental Expression of SMARCAL1

Abstract

Schimke immuno-osseous dysplasia (OMIM 242900) is an uncommon autosomal-recessive multisystem disease caused by mutations in SMARCAL1 (swi/snf-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), a gene encoding a putative chromatin remodeling protein. Neurologic manifestations identified to date relate to enhanced atherosclerosis and cerebrovascular disease. Based on a clinical survey, we determined that half of Schimke immuno-osseous dysplasia patients have a small head circumference, and 15% have social, language, motor, or cognitive abnormalities. Postmortem examination of 2 Schimke immuno-osseous dysplasia patients showed low brain weights and subtle brain histologic abnormalities suggestive of perturbed neuron-glial migration such as heterotopia, irregular cortical thickness, incomplete gyral formation, and poor definition of cortical layers. We found that SMARCAL1 is highly expressed in the developing and adult mouse and human brain, including neural precursors and neuronal lineage cells. These observations suggest that SMARCAL1 deficiency may influence brain development and function in addition to its previously recognized effect on cerebral circulation.

The SIOD disorder protein SMARCAL1 is an RPA-interacting protein involved in replication fork restart

“…Additionally, SMARCAL1-deficient cells progress through late S/G2 more slowly than wild-type cells and exhibit delayed restart of DNA replication following replication stress or DNA damage. Consistent with these results, SMARCAL1 has been implicated in cellular proliferation, as mouse neurospheres depleted of SMARCAL1 exhibit defective growth (Deguchi et al 2008). Together, our results suggest that SMARCAL1 functions at stalled or collapsed replication forks to promote their stability or to directly facilitate the restart of replication.…”

“…Rabbit polyclonal anti-RPA1 (1:100; Cell Signaling, #2267), anti-RPA2 (1:1000; Bethyl, A300-244A), and anti-SMARCAL1 (1:1000; gift from C. Boerkoel;Deguchi et al 2008); goat polyclonal anti-CtIP (1:500; Santa Cruz Biotechnologies, sc5970); and mouse monoclonal anti-HA (1:1000; Covance, clone 16B12), anti-RPA3 (1:100; GeneTex, clone 1F4), and anti-SMARCAL1 (1:500; Abnova, clone B01) were used in Western blotting.…”

“…Other members of the SNF2 family, such as CSB, SWR1, RAD54, and RAD5, have also been implicated in the repair of various types of DNA lesions . SMARCAL1 (SWI/SNF-related, matrix associated, actindependent regulator of chromatin, subfamily a-like 1), or HARP (HepA-related protein), is a distant SNF2 family member that is mutated in Schimke immunoosseous dysplasia (SIOD), a pleiotropic syndrome characterized by skeletal dysplasia, renal failure, T-cell immunodeficiency and, in approximately one-half of cases, microcephaly (Coleman et al 2000;Boerkoel et al 2002;Flaus et al 2006;Deguchi et al 2008). Characterization of many of the known SMARCAL1 mutations from SIOD patients revealed that a large number altered the ATPase activity of the protein, demonstrating that it is required for normal SMARCAL1 function (Elizondo et al 2009).…”

Gene Clusters, Molecular Evolution and Disease: A Speculation

“…SIOD is an autosomal recessive disorder of T-cell immunodeficiency, spondyloepiphyseal dysplasia, renal failure, hypothyroidism, episodic cerebral ischemia, and bone marrow failure. Both clinical and cell culture studies suggest that functional SMARCAL1 protein is required for the proliferation of many of the affected tissues [114][115][116]. Consistent with its role as an annealing DNA helicase [117], the SMARCAL1 protein binds nucleosomes and has DNA-dependent, RNA-independent, ATPase activity [118,119].…”

HARPing on about the DNA damage response during replication: Figure 1.

“…SIOD patients display varied severities of the disease and a diverse range of symptoms, but relatively invariant features include kidney failure, T-cell immunodeficiency, and skeletal dysplasia (Spranger et al 1991;Boerkoel et al 2000). In some cases, microcephaly also results (Deguchi et al 2008), a phenotype that is often associated with defects in the DNA damage response at the organismal level (O 'Driscoll and Jeggo 2008). Together, these intriguing phenotypes as well as the unique biochemical activity of HARP make it fascinating for further study.…”