In a continuous review of the literature during the past 10 years, I searched PubMed for review articles published in English with the terms “kidney” and “molecular genetics”. Additionally, I searched OMIM for “renal tubular AND number sign”. Recent review articles about the topic were considered.
SeriesGenetic kidney diseases
Section snippets
Genetic disease causality
In single-gene disorders, also known as monogenic diseases, a mutation in one gene (of about 25 000 genes) is sufficient to cause the disease. Conversely, polygenic disorders are caused by mutations in several different genes. The mode of inheritance determines the degree of genetic causality (table 1). At one end of the range there is tight genotype-phenotype correlation in monogenic recessive diseases, so that the disease phenotype is almost exclusively determined by the single-gene causative
Mutation analysis
Because of the strong genotype-phenotype correlation of almost 100% that is noted in recessive single-gene renal disorders, mutation analysis shows the primary cause of the disease, allows prenatal diagnostic tests to be done, and has a high diagnostic and prognostic value. Identification of a mutation in a known recessive disease gene might be seen as the most robust diagnostic example of personalised medicine, because the recessive mutation conveys an almost 100% risk that the patient will
Common and polygenic renal disorders
In single-gene disorders, the penetrance is close to 100% (table 1), with the exception of age-dependent penetrance, and, in dominant diseases, with the exceptions of incomplete penetrance (skipping of a generation) and variable expression (different extent and severity of organ involvement). By contrast, in polygenic diseases, several mutated alleles in different genes have to act in concert to cause disease (table 1).
The clear-cut lines between single-gene and polygenic diseases have become
Future directions
The causative genes have been identified in only about 2600 of nearly 5400 known Mendelian disorders in man, whereas the disease-causing gene is still elusive in roughly 2800 disorders. Two novel techniques were developed that might greatly assist the rapid discovery of causative genes for single-gene disorders. One of these techniques is total human exome capture, in which hybridisation is used to capture the entire exome of roughly 180 000 protein-encoding human exons.97 Exome capture is
Search strategy and selection criteria
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Rearrangement of the human CDC5L gene by a t(6;19)(p21;q13.1) in a patient with multicystic renal dysplasia
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Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux
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SLIT2-mediated ROBO2 signaling restricts kidney induction to a single site
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Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome
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Genetic mapping in human disease
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NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome
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Novel mutations in NPHS2 detected in both familial and sporadic steroid-resistant nephrotic syndrome
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Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible
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A novel TRPC6 mutation that causes childhood FSGS
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Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2)
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Specific podocin mutations correlate with age of onset in steroid-resistant nephrotic syndrome
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Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome
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Sensitive cilia set up the kidney
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Molecular diagnostics of ADPKD coming of age
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Die familiäre juvenile nephronophthise
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Nephronophthisis-associated ciliopathies
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NEK8 mutations affect ciliary and centrosomal localization and may cause nephronophthisis
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Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis
Nat Genet
The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4
Nat Genet
A novel ciliary IQ domain protein, NPHP5, is mutated in Senior-Loken syndrome (nephronophthisis with retinitis pigmentosa), and interacts with RPGR and calmodulin
Nat Genet
Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis
Nat Genet
Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination
Nat Genet
A gene mutated in nephronophthisis and retinitis pigmentosa encodes a novel protein, nephroretinin, conserved in evolution
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A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1
Nat Genet
The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that interacts with nephrocystin
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The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome
Nat Genet
Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy
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BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus
Nat Genet
MKKS/BBS6, a divergent chaperonin-like protein linked to the obesity disorder Bardet-Biedl syndrome, is a novel centrosomal component required for cytokinesis
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Cloning and characterization of a splice variant of human Bardet-Biedl syndrome 4 gene (BBS4)
DNA Seq
Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome
Nat Genet
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