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Clinical Manifestations of Alport Syndrome-Diffuse Leiomyomatosis Patients With Contiguous Gene Deletions in COL4A6 and COL4A5

ABSTRACT: Alport syndrome-diffuse leiomyomatosis is a rare type of X-linked Alport syndrome resulting from contiguous deletions of 5′ exons of COL4A5 and COL4A6. Studies have suggested that the occurrence of diffuse leiomyomatosis is associated with the characteristic localisation of the COL4A6 gene deletion break point. An electronic database was searched for all studies accessing AS-DL to analyze the clinical characteristics, gene deletion break points of patients with AS-DL, and the pathogenesis of AS-DL. It was found that the proportion of de novo mutations of AS-DL was significantly higher in female probands than male probands (78 vs. 44%). Female patients with AS-DL had a mild clinical presentation. The incidence of proteinuria and ocular abnormalities was much lower in female probands than in male probands, and there was generally no sensorineural hearing loss or chronic kidney disease (CKD), which progressed to Stage 3 in female probands. The contiguous deletion of the 5' exons of COL4A5 and COL4A6, with the break point within the intron 3 of COL4A6, was the critical genetic defect causing AS-DL. However, the pathogenesis of characteristic deletion of COL4A6 that contributes to diffuse leiomyomatosis is still unknown. In addition, characteristic contiguous deletion of COL4A5 and COL4A6 genes in AS-DL may be related to transposed elements (TEs).

SUBMITTER: Zhou X

PROVIDER: S-EPMC8578185 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and objectivesX-linked Alport syndrome is caused by mutations in the COL4A5 gene. Although many COL4A5 mutations have been detected, the mutation detection rate has been unsatisfactory. Some men with X-linked Alport syndrome show a relatively mild phenotype, but molecular basis investigations have rarely been conducted to clarify the underlying mechanism.Design, setting, participants, & measurementsIn total, 152 patients with X-linked Alport syndrome who were suspected of having Alport syndrome through clinical and pathologic investigations and referred to the hospital for mutational analysis between January of 2006 and January of 2013 were genetically diagnosed. Among those patients, 22 patients had suspected splice site mutations. Transcripts are routinely examined when suspected splice site mutations for abnormal transcripts are detected; 11 of them showed expected exon skipping, but others showed aberrant splicing patterns. The mutation detection strategy had two steps: (1) genomic DNA analysis using PCR and direct sequencing and (2) mRNA analysis using RT-PCR to detect RNA processing abnormalities.ResultsSix splicing consensus site mutations resulting in aberrant splicing patterns, one exonic mutation leading to exon skipping, and four deep intronic mutations producing cryptic splice site activation were identified. Interestingly, one case produced a cryptic splice site with a single nucleotide substitution in the deep intron that led to intronic exonization containing a stop codon; however, the patient showed a clearly milder phenotype for X-linked Alport syndrome in men with a truncating mutation. mRNA extracted from the kidney showed both normal and abnormal transcripts, with the normal transcript resulting in the milder phenotype. This novel mechanism leads to mild clinical characteristics.ConclusionsThis report highlights the importance of analyzing transcripts to enhance the mutation detection rate and provides insight into genotype-phenotype correlations. This approach can clarify the cause of atypically mild phenotypes in X-linked Alport syndrome.

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Clinical Manifestations of Alport Syndrome-Diffuse Leiomyomatosis Patients With Contiguous Gene Deletions in COL4A6 and COL4A5

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