title: R561C missense mutation in the SMARCAL1 gene associated with mild Schimke immuno-osseous dysplasia.
abstract: Autosomal-recessive Schimke immuno-osseous dysplasia (SIOD) characterized by spondyloepiphyseal dysplasia, focal-segmental glomerulosclerosis (FSGS), T-cell immunodeficiency and facial dysmorphism is caused by defects in the SMARCAL1 gene. The gene product is involved in the transcriptional regulation of other genes. A 12-year-old boy of consanginous Turkish descent developed disproportionate short stature from spondyloepiphyseal dysplasia at the age of 6 and nephrotic syndrome at the age of 10 years. Renal biopsy revealed FSGS, the kidney function was normal, T-lymphocytes were diminished without infectious complications, and he has had no cerebral ischemia. Analysis of the patient's SMARCAL1 gene revealed a novel homozygous C1798T transition leading to a R561C substitution. The parents and two healthy sisters were found to be heterozygous. A younger brother, who is also homozygous for the mutation, is clinically asymptomatic and has no proteinuria at the age of 18 months. Still, his CD4 cells are diminished. For SMARCAL1 mutations a clear genotype-phenotype correlation has been reported: severe SIOD with in utero or early-childhood onset leading to end-stage renal disease within a few years is caused by nonsense, frame shift or splice mutations. Many patients die from infections and cerebrovascular insults during childhood. Mild SIOD manifests later and progresses more slowly without infectious or cerebral vascular complications--the underlying defect being missense mutations in all three patients reported so far. The novel R561C missense mutation in our patient with mild SIOD is additional evidence for the genotype-phenotype correlation reported for SMARCAL1 mutations.
authors.affiliation: Department of Pediatrics, Vrije University Medical Center, Amsterdam, The Netherlands. bokenkamp@VUmc.nl
authors.forename: Arend
authors.initials: A
authors.lastname: Bökenkamp
authors.forename: Miranda
authors.initials: M
authors.lastname: deJong
authors.forename: Joanna A E
authors.initials: JA
authors.lastname: van Wijk
authors.forename: Diana
authors.initials: D
authors.lastname: Block
authors.forename: Johanna M
authors.initials: JM
authors.lastname: van Hagen
authors.forename: Michael
authors.initials: M
authors.lastname: Ludwig
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D001120:Arginine / Q000378:metabolism; D001483:Base Sequence; D001706:Biopsy; D002648:Child; D003241:Consanguinity; D004265:DNA Helicases / Q000737:chemistry / Q000235:genetics*; D004252:DNA Mutational Analysis; D004656:Enalapril / Q000627:therapeutic use; D005091:Exons; D005500:Follow-Up Studies; D005808:Genes, Recessive; D008040:Genetic Linkage; D006720:Homozygote; D006801:Humans; D007668:Kidney / Q000601:surgery; D019808:Losartan / Q000627:therapeutic use; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009404:Nephrotic Syndrome; D010009:Osteochondrodysplasias / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D017434:Protein Structure, Tertiary; D011859:Radiography; D017386:Sequence Homology, Amino Acid; D013997:Time Factors; D016896:Treatment Outcome; D014421:Turkey / Q000208:ethnology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D004656:Enalapril; D001120:Arginine; C412482:SMARCAL1 protein, human; D004265:DNA Helicases; D019808:Losartan