This report describes Schimke immuno-osseous dysplasia (SIOD); SIOD exhibits incompletely penetrant autosomal recessive inheritance. The human gene implicated in this disease is SMARCAL1, a member of the SWI/SNF family which encodes a DNA-annealing helicase with roles in DNA replication fork restart, DNA repair, and gene expression modulation. There is a single orthologous gene in Drosophila, Marcal1, for which loss-of-function alleles created by imprecise excision of an insertion or by targeted recombination, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated.
Multiple UAS constructs of the human Hsap\SMARCAL1 gene have been introduced into flies, including wild-type and an extensive number of variants implicated in SIOD. Variant(s) implicated in human disease tested (as transgenic human gene, SMARCAL1): the A468P, I548N, S579L, R586W, R644W, R645C, K647T, K647Q, T705I, R764Q, and R820H variant forms have been introduced into flies. In these experiments, disease severity was shown to be inversely proportionate to overall SMARCAL1 activity.
Animals homozygous for amorphic or deletion mutations of Dmel\Marcal1 survive to adulthood; they exhibit a temperature-sensitive reduction in lifespan and abnormal expression of heat shock genes after a heat pulse. It is postulated that the modified expression of multiple genes in multiple different tissues underlies the pathogenic phenotypes of SIOD; this is supported by modified patterns of gene expression observed in flies. Ubiquitous overexpression of Marcal1 or Hsap\SMARCAL1 results in a visible wing vein phenotype, which has allowed screens for genetic interactions; many of the interacting genes encode transcriptional regulators, including epigenetic regulators. For specific information on genetic interactions, see the Marcal1 gene report.
[updated Aug. 2018 by FlyBase; FBrf0222196]
[SCHIMKE IMMUNOOSSEOUS DYSPLASIA; SIOD](https://omim.org/entry/242900)
[SWI/SNF-RELATED, MATRIX-ASSOCIATED, ACTIN-DEPENDENT REGULATOR OF CHROMATIN, SUBFAMILY A-LIKE PROTEIN 1; SMARCAL1](https://omim.org/entry/606622)
Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive multisystem disorder characterized by spondyloepiphyseal dysplasia (SED) resulting in short stature, nephropathy, and T-cell deficiency. Nearly all affected individuals have progressive steroid-resistant nephropathy, usually developing within five years of the diagnosis of growth failure and terminating with end-stage renal disease (ESRD). The majority of tested individuals have T-cell deficiency and an associated risk for opportunistic infection, a common cause of death. SIOD involves a spectrum that ranges from an infantile or severe early-onset form with death early in life to a juvenile or milder later-onset form with survival into adulthood if renal disease is appropriately treated. [Gene Reviews, Schimke Immunoosseous Dysplasia, 2018.08.23]
The clinical phenotype of Schimke immunoosseous dysplasia is characterized by growth retardation, renal failure, recurrent infections, cerebral infarcts, and skin pigmentation beginning in childhood. [from MIM:242900; 2018.08.23]
Ongoing correlations of genotype to phenotype have shown that genotype does not predict disease severity or outcome either within or among families. The phenotypic heterogeneity and variable expressivity suggest that SIOD is modified by factors such as environment, epigenetics, and oligogenic inheritance. [Gene Reviews, Schimke Immunoosseous Dysplasia, 2018.08.23]
Schimke immunoosseous dysplasia (SIOD) is caused by homozygous or compound heterozygous mutation in the SMARCAL1 gene. [from MIM:242900; 2018.08.23]
SMARCAL1 encodes a member of the SWI/SNF family of proteins. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The SMARCAL1 protein acts throughout the genome to reanneal stably unwound DNA, performing the opposite reaction of many enzymes, such as helicases and polymerases, that unwind DNA. [Gene Cards, SMARCAL1; 2018.08.23]
SMARCAL1 encodes a DNA-annealing helicase with roles in DNA replication fork restart, DNA repair, and gene expression modulation (FBrf0234417 and references cited therein).
SMARCAL1 encodes a member of the well-conserved SNF2 family of proteins; members of this family are components of multiprotein complexes involved in the remodeling of chromatin to change nucleosome compaction for gene regulation, replication, recombination, and DNA repair. [from MIM:606622; 2018.08.23]
One to one: 1 human to 1 Drosophila.
High-scoring ortholog of human SMARCAL1 (1 Drosophila to 1 human). Dmel\Marcal1 shares 35% identity and 52% similarity with the human gene.
