Proteinuric renal disease

Gene: PDSS2

Green List (high evidence)

Comment on list classification: Upgraded from red to green. 4 cases plus a mouse knock out model.

Created: 9 Jul 2019, 2:40 p.m. | Last Modified: 9 Jul 2019, 2:53 p.m.

Panel Version: 1.221

The gene is associated with Coenzyme Q10 deficiency, primary, 3 (#614652) in OMIM and COENZYME Q10 DEFICIENCY, PRIMARY, 3 (confirmed) in Gene2Phenotype.

PMID: 29032433 - Iványi et al 2018 - 1 case - male child of healthy, nonconsanguineous Caucasian parents. At 7 months of age he had general edema, muscle hypotonia, mild inspiratory stridor, and global developmental delay. He did not react to auditory stimuli, and they detected no tracking and focusing eye movements. Urinalysis revealed proteinuria. A heterozygous missense mutation in the PDSS2 gene in exon 3 was found (c.485A > G, p.His162Arg) (maternally inherited) along with a heterozygous 2923-bp deletion that affected a part of exon 8 in the PDSS2 gene. The paternal allele is the NM_020381.3:c.1042_1148-2816del, which causes a 107-base long deletion of exon 8. Despite high-dose CoQ10 treatment he died at 8 months of age.

PMID: 25349199 - Sadowski et al 2015 - 2 cases with homozygous missense changes in PDSS2 in patients with Steroid-resistant nephrotic syndrome. They performed exon sequencing of NPHS2 and WT1 for 1783 unrelated, international families with Steroid-resistant nephrotic syndrome (SRNS) and then examined all patients by microfluidic multiplex PCR and next-generation sequencing for all 27 genes known to cause SRNS if mutated. 2 families were molecularly diagnosed with a causative variant in PDSS2 by multiplex PCR (c.1145C>T,p.Ser382Leu and c.1151C>A, p.Ala384Asp).

PMID: 23926186 - Gasser et al 2013 - genotyped 377 patients with primary Focal segmental glomerulosclerosis (FSGS) or collapsing glomerulopathy, together with 900 controls, for 9 single-nucleotide polymorphisms in the PDSS2 gene in a case-control study. The nine selected SNPs were distributed at approximately equal distances across the PDSS2 gene. All the SNPs that were genotyped occurred within noncoding regions of the gene. They demonstrated that homozygous genotypes for variant alleles for the PDSS2 gene were more common in FSGS patients than controls and that a single haplotype containing three of these SNPs was more common in European American, but not African American, FSGS patients, suggesting that PDSS2 may be an FSGS susceptibility gene.

PMID:17186472 - Lopez et al 2006 - 1 family with child who presented with neonatal pneumonia and hypotonia, developed refractory left-sided seizures with secondary generalization, and became progressively floppy. At age 7 mo, severe episodic vomiting prompted duodenal tube feeding, and was diagnosed with nephrotic syndrome due to low serum albumin and massive proteinuria. They found two nonsynonymous nucleotide changes in PDSS2, each inherited from one parent. Functional tests on cultured patient fibroblast indicate that endogenous levels of decaprenyl diphosphate are reduced.

Mouse model:
PMID: 18437205 - Peng et al 2008 - Kidney disease in mice with missense Pdss2(kd/kd) genotype can be attributed to a mitochondrial CoQ biosynthetic defect. Levels of CoQ9 and CoQ10 in kidney homogenates from B6.Pdss2(kd/kd) mutants were significantly lower than those in B6 control mice. Disease manifestations originate specifically in glomerular podocytes, as renal disease is seen in Podocin/cre,Pdss2(loxP/loxP) knockout mice but not in conditional knockouts targeted to renal tubular epithelium, monocytes, or hepatocytes.

Summary:
4 cases of children with nephrotic syndrome and homozygous or compound heterozygous variants in PDSS2. In two cases the variants are reported to segregate with the disease in the family. Additional evidence from a case control study that PDSS2 is a FSGS susceptibility gene and from a mouse Pdss2 knockout model.

Created: 9 Jul 2019, 2:39 p.m. | Last Modified: 9 Jul 2019, 2:39 p.m.

Panel Version: 1.218

This gene was part of an initial gene list collated by Elizabeth Watson, North Bristol NHS Trust, February 2019 on behalf of the GMS Renal Specialist Test Group. Gene Symbol submitted: PDSS2; Suggested initial gene rating: green; Evidence for inclusion: PMID: 23926186 ; Other comments: SRNS is hallmark renal feature of Coenzyme 10 deficiency. Multiple reports in literature.

Created: 4 Feb 2019, 10:41 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Coenzyme Q10 deficiency, primary, 3 #614652

Publications

• PMID: 23926186

Variants in this GENE are reported as part of current diagnostic practice

Comment on list classification: Insufficient evidence - only 1 case report.

Created: 27 May 2016, 12:41 p.m.

I don't know

Currently on UK diagnostic panel, 1 VUS, no definite positive cases over 300 tested
Listed in several reviews

Created: 19 Oct 2015, 3:04 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Leigh syndrome

Variants in this GENE are reported as part of current diagnostic practice