Fetal megacystis‐microcolon: Genetic mutational spectrum and identification of PDCL3 as a novel candidate gene

Abstract

Megacystis‐microcolon‐intestinal‐hypoperistalsis syndrome (MMIHS) is a severe congenital visceral myopathy characterized by an abdominal distension due to a large non‐obstructed urinary bladder, a microcolon and intestinal hypo‐ or aperistalsis. Most of the patients described to date carry a sporadic heterozygous variant in ACTG2. More recently, recessive forms have been reported and mutations in MYH11, LMOD1, MYLK and MYL9 have been described at the molecular level. In the present report, we describe five patients carrying a recurrent heterozygous variant in ACTG2. Exome sequencing performed in four families allowed us to identify the genetic cause in three. In two families, we identified variants in MMIHS causal genes, respectively a nonsense homozygous variant in MYH11 and a previously described homozygous deletion in MYL9. Finally, we identified compound heterozygous variants in a novel candidate gene, PDCL3, c.[143_144del];[380G>A], p.[(Tyr48Ter)];[(Cys127Tyr)]. After cDNA analysis, a complete absence of PDLC3 expression was observed in affected individuals, indicating that both mutated transcripts were unstable and prone to mediated mRNA decay. PDCL3 encodes a protein involved in the folding of actin, a key step in thin filament formation. Presumably, loss‐of‐function of this protein affects the contractility of smooth muscle tissues, making PDCL3 an excellent candidate gene for autosomal recessive forms of MMIHS.

Visceral myopathy: clinical syndromes, genetics, pathophysiology, and fall of the cytoskeleton

“…Therefore, a mutation that eliminates or disrupts MYL9 would likely reduce SMC contractility. There are two reported MYL9 mutations associated with MMIHS (12,36,57). One mutation is a large homozygous deletion that removes the last exon (exon 4) from the two MYL9 transcripts (36).…”

“…Unsurprisingly, mutations in genes encoding these contractile apparatus proteins are common genetic causes of visceral myopathy. Here, we summarize data about disease pathophysiology and cell biology, linking clinical manifesta-MYLK (35), LMOD1 (35), MYL9 (12,36), and FLNA (37). Myotonic dystrophy type 1, Duchenne muscular dystrophy, and oculogastrointestinal muscular dystrophy also cause CIPO as do scleroderma, systemic lupus erythematosus, dermatomyositis, polymyositis, amyloidosis, ceroidosis, and mitochondrial diseases such as mitochondrial neuro-gastrointestinal-encephalomyopathy (MNGIE) (1).…”

Mutations in Hsp90 Cochaperones Result in a Wide Variety of Human Disorders

“…PhLP2A (encoded by PDCL3) is an Hsp90 interacting protein that does not contain either TPR or CS domain that is involved in the folding of actin ( Krzemien-Ojak et al, 2017 ). Loss of function alleles of PDCL3 were identified in patients with megacystis-microcolon-intestinal-hypoperistalsis syndrome, which affects muscles in the bladder and intestines ( Billon et al, 2020 ). Integrins are transmembrane links between extracellular contacts and the actin microfilaments.…”

Phosducin-like 3 is a novel prognostic and onco-immunological biomarker in glioma: A multi-omics analysis with experimental verification

“…This phenomenon is regulated by both hypoxia induction and N-terminal methionine acetylation of PDCL3 itself ( 13 ). Gene mutations or aberrant expression of PDCL3 have been shown to be associated with Alzheimer’s disease ( 14 ), fetal macrovesicular microcolon ( 15 ), and severe dengue infections ( 16 ). In addition, another member of the phosducin-like protein family, phosducin-like protein 3 (PhLP3), also known as thioredoxin domain-containing 9 (TXNDC9), was proven to be an oncogene that promotes the malignant progression of many types of cancers, including prostate cancer ( 17 ), hepatocellular carcinoma ( 17 ), colorectal adenocarcinoma ( 18 ), gastric cancer ( 19 ) and malignant glioma ( 20 ).…”