Relevance to Autism

A maternally-inherited hemizygous frameshift variant in the CUL4B gene was recently identified in a Chinese male presenting with severe-profound global developmental delay/intellectual disability and a comorbid diagnosis of ASD (Wu et al., 2024). A de novo splice-site variant in this gene had previously been identified in a male ASD proband from a simplex family from the MSSNG cohort (Zhou et al., 2022). Additional maternally-inherited variants affecting CUL4B have been reported in European patients presenting with intellectual disability and either autistic features or stereotypy (Redin et al., 2014; Lopes et al., 2019).

Molecular Function

This gene is a member of the cullin family. The encoded protein forms a complex that functions as an E3 ubiquitin ligase and catalyzes the polyubiquitination of specific protein substrates in the cell. The protein interacts with a ring finger protein, and is required for the proteolysis of several regulators of DNA replication including chromatin licensing and DNA replication factor 1 and cyclin E. Mutations in the CUL4B gene are responsible for the Cabezas type of X-linked syndromic intellectual developmental disorder (MRXSC; OMIM 300354), which is characterized primarily by short stature, hypogonadism, and abnormal gait, with other more variable features such as speech delay, prominent lower lip, and tremor.

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