A novel SMARCAL1 mutation associated with a mild phenotype of Schimke Immuno-Osseus Dysplasia (SIOD)


Schimke Immuno-Osseus Dysplasia (SIOD; MIM_242900) is a rare autosomal recessive multisystem disorder, firstly described in 1971 [1] [2]. Typical findings of SIOD are spondyloepiphyseal dysplasia with disproportionate growth failure, typical facial appearance, nephrotic syndrome with focal segmental glomerulosclerosis (FSGS) and progressive renal failure, recurrent lymphopenia, T-cell immunodeficiency, and pigment naevi [3] (full text). Other features include hypothyroidism, episodic cerebral ischaemia and bone marrow failure [4]. The SIOD phenotype may range from a severe variant with in utero onset to a milder form with later onset [5] (full text) [6]. SIOD is caused by mutations in the gene encoding HepA-related protein (HARP) also known as SMARCAL1 (SWI/SNF-related, matrix associated, actin-dependent regulator of chromatin, subfamily a-like 1), a protein homologous to the sucrose non fermenting type 2 (SNF2) family of chromatin-remodeling proteins, required for transcriptional regulation, replication, repair, recombination, and covalent modification [7] [8] (full text) [9]). Biallelic putative loss of function mutations in SMARCAL1 gene are the only identified causes of SIOD, however approximately half of patients referred for molecular studies have no detectable mutations in the coding region of this gene, thus environmental, genetic, or epigenetic modifiers and the existence of endophenotypes of SIOD have been hypothesized [10].

Here, we report the clinical and genetic diagnosis of a 5-years old girl with SIOD, referred to our Center because of nephrotic-range proteinuria occasionally detected during the follow-up for congenital hypothyroidism.


The patient was born at 29 week of gestation as the first child of healthy non-consanguineous Italian parents. Her birthweight was 720g (<3rd percentile). Congenital hypothyroidism was quickly diagnosed and substitutive therapy was started at birth time. At 5-years, because of onset of proteinuria, she was referred to our Pediatric Nephrology Center. At clinical examination she had disproportionately short stature, dorsolumbar kyphoscoliosis, fine hair, pale skin, low nasal bridge. She had normal intelligence and never had severe infections, migraines or transient ischemic attacks. Laboratory data showed nephrotic range proteinuria (1,7 g/die; 125 mg/kg/die) and normal renal function (creatinine clearance 84,75 ml/min, according to the Schwartz-formula). Lymphopenia with T-cell deficiency was also detected. Skeletal radiograph revealed dorsolumbar kyphoscoliosis with unbalanced iliac crests. The renal biopsy was performed and revealed FSGS (Figure 1A-B). Treatment with ramipril and irbesartan resulted in a reduction of proteinuria (0,104 g/die). After two-years follow-up, the patient displays normal renal function without proteinuria and no episodes of infection or cerebrovascular complication.

On the basis of clinical and laboratory findings, a diagnosis of SIOD was suspected. After obtaining informed consent for genetic studies from all family members, genomic DNA was purified from peripheral blood samples. Mutational analysis of SMARCAL1 gene (NM_014140.3; GeneID:50485) was performed by PCR and bidirectional sequencing of the coding exons and intron/exon flanking regions. Sequence analysis revealed that patient was compound heterozygous for two mutations (Figure 2): a novel missense mutation in exon 3 (c.740G>C), resulting in an arginine-to-proline substitution(p.R247P), inherited by the mother; and a nonsense paternally-derived mutation in exon 17 (c.2542G>T) resulting in the substitution of E848 with a stop codon (p.E848X) (9). The healthy brother was wild type for detected mutations (data not shown).


SIOD is an autosomal recessive pleiotropic disorder caused by mutation in the SMARCAL1 gene (1,2). The pathogenesis of SIOD is largely unknown. The SMARCAL1 gene encodes the HepA-related protein (HARP), a member of the SNF2 family of ATPases, acting as chromatin remodelers within multi-protein complexes [11]. This protein is an ATP-driven annealing helicase, involved in a wide range of biological functions, including transcription, DNA replication, and DNA repair. SIOD patients exhibit a continuum from mild to severe disease. Severe form is characterized by intrauterine growth retardation, severe growth failure after birth, recurrent infections, hematological abnormalities, hypothyroidism, cerebrovascular disease and often death within the first 15-years. Mild form usually displays growth failure and renal dysfunction between 8 and 12 years but patients do not suffer from infection or cerebrovascular disease (4-6). Usually, patients with SMARCAL1 biallelic missense mutations or a missense and a nonsense mutation have a milder disease. Accordingly, our patient, compound heterozygous for a novel missense mutation (p.R247P) and a well-known nonsense mutation (p.E848X) (9), displayed a mild form. The missense mutation (p.R247P) within the first HARP domain (HARP1), described for the first time in this report, is locatedin a highest-conserved site of the multi-sequence alignment (Figure 3) and is predicted to be a damaging change by SIFT (Sorting Intolerant From Tolerant) programme (http://blocks.fhcrc.org/sift/SIFT.html) with a score of 0.0 and a ‘probably damaging’ substitution by Polyphenprogramme (http://genetics.bwh.harvard.edu/pph2/) with a score of 1.000. All SNF2 proteins are characterized by the presence of SWI/SNF helicase motifs but do not always exhibit helicase activity. SMARCAL1 protein has ATP-dependent annealing helicase activity, which helps to stabilize stalled replication forks and facilitate DNA repair during replication. Recently, it was shown that the conserved tandem HARP (2HP) domain dictates this annealing helicase activity, suggesting that the HARP domains are important determinants of the SMARCAL1 enzyme specificity [12] (full text). The nonsense mutation, p.E848X, leading to a truncated SMARCAL1 protein of 847 aa, was previously reported in other SIOD patients with different ethnic origin (9).

The patient was referred to our attention because of onset of proteinuria in nephrotic range. Renal biopsy revealed a FSGS, which is the most frequent renal pathological finding associated with SIOD [13], as described in a revision of 39 SIOD cases with proteinuria. Nevertheless cases of minimal change disease, membranous nephropathy, mesangial proliferative glomerulonephritis and nephrophthisis have been also described [14]. Kidney involvement in SIOD patients displays typically proteinuria evolving to overt nephrotic syndrome, usually diagnosed between 1 year and 14 years of age (4-6,9). This genetic form of nephrotic syndrome usually does not respond to steroid treatment (6); nevertheless, transient reductions in proteinuria using ACE-inhibitors, NSAID or even cyclosporine-A have been documented (4-6,9). Our experience demonstrate that nephrotic proteinuria associated with a mild form of SIOD may respond to combined therapy with ACE-inhibitors and sartans, as previously reported (16). However most of patients, mainly severe forms, progress to ESRD between 5 and 15 years of age. No relapse of proteinuria has been described in SIOD patients after renal transplantation (16), while the evolution of cerebrovascular and infectious complications do not seem to improve after transplantation.

In summary, we report a case of SIOD compound heterozygous for a novel missense mutation and a nonsense mutation. This genotype led to a mild phenotype with renal involvement, characterized by nephrotic proteinuria, which decreased after combined therapy with ACE inhibitors and sartans.