Table 3.
Genetic causes of FSGS: Syndromic FSGS
| Gene, Locus, Inheritance | Protein | Protein Function | Syndromic Association | Response to Therapy | |
|---|---|---|---|---|---|
| MYH9 | Myosin heavy chain 9 | Protein with several important functions, including cytokinesis, cell motility, and maintenance of cell shape | Epstein–Fechtner syndrome (FSGS, sensorineural deafness, cataracts, macrothrombocytopenia, leukocyte inclusions) | Resistant to immunosuppression | |
| 22q12.3 | |||||
| AD | |||||
| KANK 1 | Kidney ankyrin repeat-containing protein 1 | Regulation Rho GTPase activity in podocytes (cell migration and shape) | Familial early-onset SRNS and intellectual disability | Resistant to immunosuppression | |
| 9p24.3 | |||||
| AR | |||||
| KANK 4 | Kidney ankyrin repeat-containing protein 4 | Regulation Rho GTPase activity in podocytes (cell migration and shape) | Familial early-onset FSGS, intellectual disability, facial dysmorphism, and atrial septal defect | Resistant to immunosuppression | |
| 1p31.3 | |||||
| AR | |||||
| ITGA3 | Integrin-α3 | Component of integrin-α3 β1 involved in podocyte-GBM interaction | NEP syndrome (early-onset FSGS, epidermolysis bullosa, and interstitial lung disease) | Resistant to immunosuppression | |
| 17q21.33 | |||||
| AR | |||||
| ITGB4 | Integrin-β4 | Component of integrin-α6 β4 involved in podocyte-GBM interaction | Early-onset FSGS, epidermolysis bullosa, and pyloric atresia | Resistant to immunosuppression | |
| 17q11 | |||||
| AR | |||||
| LAMB2 | Laminin-β2 | Extracellular matrix glycoprotein implicated in cell adhesion, differentiation, migration, signaling | Pierson Syndrome (microcoria, neuromuscular junction defects, early-onset DMS or FSGS), isolated congenital or childhood-onset SRNS | Resistant to immunosuppression | |
| 3p21 | |||||
| AR | |||||
| LMX1B | LIM homeobox transcription factor 1β | Nuclear transcription factor | Sporadic FSGS, Nail–Patella syndrome (hypoplastic or absent patella, dysplasia of elbows, dystrophic nails, frequently glaucoma) | Resistant to immunosuppression | |
| 9q34 | |||||
| AD | |||||
| PAX2 | Paired box 2 | Nuclear transcription factor | Renal coloboma syndrome (childhood-onset FSGS, optic nerve colobomas, and renal hypoplasia), isolated adult-onset FSGS | Resistant to immunosuppression | |
| 10q24 | |||||
| AD | |||||
| WT1 | Wilms tumor 1 | Nuclear transcription factor | Frasier syndrome (FSGS, gonadoblastoma, male pseudohermaphroditism), Denys–Drash syndrome (DMS, Wilms’ tumor, male pseudohermaphroditism), isolated congenital or childhood-onset DMS or FSGS | Reported patients with (partial) response to cyclosporin | |
| 11p13 | |||||
| AD | |||||
| NUP107 | Nucleoporine 107 kD | Component of the nuclear pore complex | Childhood-onset FSGS and microcephaly | Resistant to immunosuppression | |
| 12q15 | |||||
| AR | |||||
| SMARCAL1 | SMARCA-like protein | Protein with helicase and ATPase activities | Schimke immuno-osseous dysplasia (immunodeficiency, skeletal dysplasia, childhood-onset FSGS) | Resistant to immunosuppression | |
| 2q34–36 | |||||
| AR | |||||
| NXF5 | Nuclear RNA export factor 5 | Member of family of nuclear RNA export factor genes | Adult-onset FSGS and cardiac conduction disorders | Resistant to immunosuppression | |
| Xq22 | |||||
| X-linked | |||||
| COQ2 | Coenzyme Q2 4-hydroxybenzoate polyprenyl transferase | Enzyme involved in the biosynthesis of CoQ10 | Childhood-onset collapsing FSGS, encephalopathy | May respond to coenzyme Q10 | |
| 4q21.23 | |||||
| AR | |||||
| COQ6 | Coenzyme Q6 monooxygenase | Enzyme involved in the biosynthesis of CoQ10 | Early childhood-onset FSGS/DMS, sensorineural deafness | May respond to coenzyme Q10 | |
| 14q24.3 | |||||
| AR | |||||
| PDSS2 | Prenyl diphosphate synthase subunit 2 | Enzyme involved in the biosynthesis of CoQ10 | Congenital SRNS and encephalomyopathy, Leigh syndrome | May respond to coenzyme Q10 | |
| 6q21 | |||||
| AR | |||||
| ADCK4 | aarF domain containing kinase 4 | Enzyme involved in the biosynthesis of CoQ10 | Childhood and early adult–onset FSGS (neurologic manifestations in 20% of patients) | May respond to coenzyme Q10 | |
| 19q13.2 | |||||
| AR | |||||
| MTTL1 | Mitochondrially encoded tRNA leucine 1 | Mitochondrial tRNA | MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes), isolated adult-onset FSGS | Resistant to immunosuppression | |
| mtDNA | |||||
| Maternal | |||||
| MTTL2 | Mitochondrially encoded tRNA leucine 2 | Mitochondrial tRNA | MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes), isolated adult-onset FSGS | Resistant to immunosuppression | |
| mtDNA | |||||
| Maternal | |||||
| MTTY | Mitochondrially encoded tRNA tyrosine | Mitochondrial tRNA | MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes), isolated adult-onset FSGS | Resistant to immunosuppression | |
| mtDNA | |||||
| Maternal | |||||
| EYA1 | Eyes absent homolog 1 | Transcriptional activator involved in kidney, branchial arches, eye and ear development | Adult-onset FSGS and Branchio-Oto-Renal syndrome (abnormalities in branchial, ear and renal development) | Resistant to immunosuppression | |
| 8q13.3 | |||||
| AD | |||||
| LMNA | Lamin A/C | Component of the inner nuclear membrane | Familial partial lipodystrophy with adult-onset FSGS | Resistant to immunosuppression | |
| 1q21.2-q21.3 | |||||
| AD | |||||
| SCARB2 | Scavenger receptor class B member 2 | Type 3 glycoprotein located primarily in limiting membranes of lysosomes and endosomes | Action myoclonus-renal failure syndrome (ataxia, myoclonus, collapsing FSGS) | Resistant to immunosuppression | |
| 4q13–21 | |||||
| AR | |||||
| COL4A3 | α3 type 4 collagen | Subunit of type 4 collagen (main component of GBM) | Alport syndrome, familial/sporadic FSGS | Resistant to immunosuppression | |
| 2q36–37 | |||||
| AR | |||||
| COL4A4 | α4 type 4 collagen | Subunit of type 4 collagen (main component of GBM) | Alport syndrome, familial/sporadic FSGS | Resistant to immunosuppression | |
| 2q35–37 | |||||
| AR | |||||
| COL4A5 | α5 type 4 collagen | Subunit of type 4 collagen (main component of GBM) | Alport syndrome, familial/sporadic FSGS | Resistant to immunosuppression | |
| Xq22 | |||||
| X-linked | |||||
| CUBN | Cubilin | Receptor for intrinsic factor-vitamin B12 complexes, role in reabsorption of albumin at renal tubular compartment | Childhood-onset SRNS and megaloblastic anemia, rarely associated with urinary tract malformation (Imerslund–Gräsbeck syndrome) | May respond to vitamin B12 | |
| 10p12.31 | |||||
| AR | |||||
| WDR73 | WD repeat domain 73 | Scaffold protein for the assembly of protein complexes | Childhood-onset SRNS and Galloway–Mowat syndrome (microcephaly and developmental delay) | Resistant to immunosuppression | |
| 15q22 | |||||
| AR | |||||
| ALG1 | Asparagine-linked glycosylation 1 | Catalyzes the first mannosylation step in the biosynthesis of lipid-linked oligosaccharides | Congenital nephrotic syndrome in setting of disorder of glycosylation type 1-k | Resistant to immunosuppression | |
| 16p13.3 | |||||
| AR | |||||
| PMM2 | Phosphomannomutase 2 | Synthesis of dolichol-P-oligosaccharides | Childhood-onset SRNS and deficient glycoprotein syndrome type 1 | Resistant to immunosuppression | |
| 16p13.3 | |||||
| AR | |||||
| CD151 | Tetraspanin CD151 | Member of the transmembrane 4 superfamily, cell-surface proteins | Childhood-onset FSGS and bullous skin lesions, sensorineural deafness, β-thalassemia | Resistant to immunosuppression | |
| 11p15.5 | |||||
| AR | |||||
| CRB2 | Crumbs Homolog 2 | Regulation of podocyte cell polarity, differentiation and protein trafficking of slit diaphragm components | Familial childhood-onset FSGS, congenital nephrotic syndrome and cerebral ventriculomegaly | Resistant to immunosuppression | |
| 9q33.4 | |||||
| AR | |||||
| INF2 | Inverted formin 2 | Member of the formin family, function in de- and polymerization of actin filaments | Familial or sporadic adolescence and adult-onset FSGS, association with Charcot–Marie–Tooth disease | Resistant to immunosuppression | |
| 14q32.33 | |||||
| AD | |||||
| SGPL1 | Sphingosine-1-phosphate lyase | Enzyme involved in sphingolipid catabolic pathway | Familial and sporadic congenital nephrotic syndrome or childhood-onset FSGS, association with adrenal insufficiency, ichthyosis, immunodeficiency, and neurologic defects | Resistant to immunosuppression | |
| 10q22 | |||||
| AR | |||||
| ZMPSTE24 | Zinc Metalloproteinase Ste 24 | Enzyme involved in degradation of prelamin A | Young adult–onset sporadic FSGS, associated with mandibuloacral dysplasia | Likely resistant to immunosuppression | |
| 1p34.2 | |||||
| AR | |||||
AD, autosomal dominant; AR, autosomal recessive; SRNS, steroid-resistant nephrotic syndrome; NEP, Nephrotic syndrome, epidermolysis bullosa and pulmonary disease; DMS, diffuse mesangial sclerosis; mtDNA, mitochondrial DNA; tRNA, transfer RNA; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.