Galloway–Mowat syndrome
Rare genetic disorder with hiatal hernia, microcephaly, and nephrotic syndrome.
Galloway–Mowat syndrome is an extremely uncommon genetic condition passed down in an autosomal recessive pattern. Its main features include a hiatal hernia, an abnormally small head (microcephaly), and nephrotic syndrome. The exact genetic cause has not been fully pinned down, but the problem appears to lie in the KEOPS/EKC complex—a set of proteins found across bacteria, archaea, and eukaryotes that is highly similar across species. Studies of 37 cases have turned up mutations in four genes (OSGEP, TP53RK, TPRKB, and LAGE3) that code for parts of this complex. The complex’s exact job is still being worked out, but it seems to be involved in a specific step of tRNA modification: adding a chemical group to a particular spot on certain tRNAs. The enzyme OSGEP, along with other KEOPS complex components, carries out this step, and mutations in these genes can lead to the syndrome. While changes in podocyte proteins like nephrin, alpha-actinin 4, and podocin are linked to the proteinuria and nephrotic syndrome seen in the disorder, these changes are probably a result of the underlying genetic defect rather than the root cause. As of October 2020, six different genes (OSGEP, TP53RK, TPRKB, LAGE3, WDR73, and NUP107) are known to cause the condition. Most cases are autosomal recessive, meaning a child must inherit a faulty copy from each parent, who are usually unaffected carriers. However, one gene, LAGE3, is tied to an X-linked inheritance pattern.
- Causal genes
- Six genes (OSGEP, TP53RK, TPRKB, LAGE3, WDR73, and NUP107) as of October 2020
Lore & Background
Galloway–Mowat syndrome is a very rare autosomal recessive genetic disorder. Its signs and symptoms include hiatal hernia, microcephaly, and nephrotic syndrome. The exact genetic defect is yet to be discovered, but mutations in podocyte proteins such as nephrin, alpha-actinin 4, and podocin are associated with proteinuria and nephrotic syndrome. Reduced expression of synaptopodin, GLEPP1, and nephrin is observed but is likely secondary to the underlying genetic defect (e.g., in KEOPS complex mutations).
Reader's Guide
The biochemical lesion in Galloway–Mowat syndrome appears to be in the KEOPS/EKC complex, as sequencing of 37 cases revealed mutations in the OSGEP, TP53RK, TPRKB, and LAGE3 genes, all of which encode subunits of this complex. The function of this complex is still under investigation. Additionally, the biochemical lesion appears to involve the N6-threonyl-carbamoylation of adenosine 37 of ANN-type tRNA pathway, which uses two sequentially acting enzymes—YRDC and OSGEP. Mutations in these genes lead to the syndrome. The disorder is usually autosomal recessive, requiring two copies of a defective gene, but one gene, LAGE3, is associated with X-linked inheritance. As of October 2020, multiple genes (10) are causal for the clinical symptoms.
Did You Know?
- The biochemical lesion appears to be in the KEOPS/EKC complex, which is highly conserved in bacteria, archaea, and eukaryotes.
- Mutations in the OSGEP, TP53RK, TPRKB, and LAGE3 genes have been found in 37 cases of this condition.
More in Genetic disorders with OMIM but no gene 1-24
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