A novel SMARCAL1 missense mutation that affects splicing in a severely affected Schimke immunoosseous dysplasia patient.
Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive disease characterized by skeletal dysplasia, focal segmental glomerulosclerosis, renal failure and immunodeficiency. In this work, we report the molecular studies undertaken in a severely affected SIOD patient that died at six years old due to nephropathy. The patient was screened for mutations using a targeted skeletal dysplasias panel. A homozygous novel missense mutation was identified, c.1615C > G (p.[Leu539Val]) that was predicted as mildly pathogenic by in silico pathogenicity prediction tools. However, splicing prediction software suggested that this variant may create a new splicing donor site in exon 9, which was subsequently confirmed using a minigene assay in HEK293 cells. Thus, the splicing alteration, c.1615C > G; r.1615c > g, 1615_1644del; (p.[Leu539_Ile548del]), results in the loss of 10 amino acids of the HARP-ATPase catalytic domain and the RPA-binding domain. Several studies have demonstrated a weak genotype-phenotype correlation among such patients. Thus, the molecular characterization has helped us to understand why a predicted weakly pathogenic missense mutation results in severe SIOD and should be considered in similar scenarios.
Institute of Medical & Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto Carlos III, Madrid, Spain; Multidisciplinary Skeletal dysplasia Unit (UMDE), Hospital Universitario La Paz, Madrid, Spain.
Jimena
J
Barraza-García
Institute of Medical & Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain; Multidisciplinary Skeletal dysplasia Unit (UMDE), Hospital Universitario La Paz, Madrid, Spain.
Carlos I
CI
Rivera-Pedroza
Institute of Medical & Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto Carlos III, Madrid, Spain; Multidisciplinary Skeletal dysplasia Unit (UMDE), Hospital Universitario La Paz, Madrid, Spain.
Alberta
A
Belinchón
Dept. of Pediatric Nephrology, Hospital Universitario La Paz, Madrid, Spain.
Carlota
C
Fernández-Camblor
Dept. of Pediatric Nephrology, Hospital Universitario Materno Infantil de las Palmas, Las Palmas, Canary Islands, Spain.
Blanca
B
Valenciano-Fuente
Institute of Medical & Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto Carlos III, Madrid, Spain; Multidisciplinary Skeletal dysplasia Unit (UMDE), Hospital Universitario La Paz, Madrid, Spain.
Pablo
P
Lapunzina
Institute of Medical & Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto Carlos III, Madrid, Spain; Multidisciplinary Skeletal dysplasia Unit (UMDE), Hospital Universitario La Paz, Madrid, Spain. Electronic address: karen.heath@salud.madrid.org.
Karen E
KE
Heath
D001161:Arteriosclerosis / Q000175:diagnosis* / Q000235:genetics*; D001483:Base Sequence; D004265:DNA Helicases / Q000235:genetics*; D004252:DNA Mutational Analysis; D023061:Gene Order; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000175:diagnosis* / Q000235:genetics*; D007223:Infant; D008297:Male; D020125:Mutation, Missense; D009404:Nephrotic Syndrome / Q000175:diagnosis* / Q000235:genetics*; D010009:Osteochondrodysplasias / Q000175:diagnosis* / Q000235:genetics*; D010641:Phenotype; D000081207:Primary Immunodeficiency Diseases; D011655:Pulmonary Embolism / Q000175:diagnosis* / Q000235:genetics*; D022821:RNA Splice Sites; D012326:RNA Splicing; D012720:Severity of Illness Index
D022821:RNA Splice Sites; C412482:SMARCAL1 protein, human; D004265:DNA Helicases
Immunodeficiency; Nephropathy; SIOD; SMARCAL1; Skeletal dysplasia