Abstract
Although splicing errors due to single nucleotide variants represent a common cause of monogenic disorders, only a few variants have been shown to create new splice sites in exons. Here, we report an MAP3K1 splice variant identified in two siblings with 46,XY disorder of sex development. The patients carried a maternally derived c.2254C>T variant. The variant was initially recognized as a nonsense substitution leading to nonsense-mediated mRNA decay (p.Gln752Ter); however, RT-PCR for lymphoblastoid cell lines showed that this variant created a new splice donor site and caused 39 amino acid deletion (p.Gln752_Arg790del). All transcripts from the variant allele appeared to undergo altered splicing. The two patients exhibited undermasculinized genitalia with and without hypergonadotropism. Testosterone enanthate injections and dihydrotestosterone ointment applications yielded only slight increase in their penile length. Dihydrotestosterone-induced APOD transactivation was less significant in patients’ genital skin fibroblasts compared with that in control samples. This study provides an example of nonsense-associated altered splicing, in which a highly potent exonic splice site was created. Furthermore, our data, in conjunction with the previous data indicating the association between MAP3K1 and androgen receptor signaling, imply that the combination of testicular dysgenesis and androgen insensitivity may be a unique phenotype of MAP3K1 abnormalities.
Highlights
Splicing errors due to single nucleotide variants represent a common cause of monogenic disorders, only a few variants have been shown to create new splice sites in exons
We identified a “likely pathogenic” MAP3K1 variant in two siblings with 46,XY disorders of sex development (DSD)
The c.2254C>T variant was initially recognized as a nonsense substitution leading to nonsense-mediated mRNA decay (NMD)
Summary
Splicing errors due to single nucleotide variants represent a common cause of monogenic disorders, only a few variants have been shown to create new splice sites in exons. Previous studies have suggested that ~ 10% of disease-associated SNVs in exons result in aberrant s plicing[3], these variants are typically recognized as missense, nonsense, or silent substitutions These exonic splice variants usually cause exon skipping by disrupting a splice donor/ acceptor site or an exonic splicing enhancer, and in some cases, lead to exonization of a part of intronic sequences by reducing the activity of a native splice s ite[1,2,3,4,5]. SNVs in exons can create new splice donor or acceptor sites and thereby lead to intronization of part of the exons[6] This type of splice variants has rarely been reported. This study provides a novel example of splice variants and broadens the phenotypic spectrum of MAP3K1 abnormalities
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