Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor

Abstract

We have identified three truncating, two splice-site, and three missense variants at conserved amino acids in the CUL4B gene on Xq24 in 8 of 250 families with X-linked mental retardation (XLMR). During affected subjects' adolescence, a syndrome emerged with delayed puberty, hypogonadism, relative macrocephaly, moderate short stature, central obesity, unprovoked aggressive outbursts, fine intention tremor, pes cavus, and abnormalities of the toes. This syndrome was first described by Cazebas et al., in a family that was included in our study and that carried a CUL4B missense variant. CUL4B is a ubiquitin E3 ligase subunit implicated in the regulation of several biological processes, and CUL4B is the first XLMR gene that encodes an E3 ubiquitin ligase. The relatively high frequency of CUL4B mutations in this series indicates that it is one of the most commonly mutated genes underlying XLMR and suggests that its introduction into clinical diagnostics should be a high priority.

Figure 1.

Families with mutations in CUL4B. Below the pedigree for each family, a wild-type (wt) and a mutant (mut) representative trace are shown. The position of the mutation is indicated by an arrow, and the numbering is according to reference sequences (GenBank accession numbers NM_003588 and NP_003579).

Figure 2.

a, Schematic representation of the genomic structure of CUL4B, with positions of mutations found in eight families with XLMR. b, Schematic representation of the protein sequence. The cullin domain is marked, and the positions of the eight mutations are indicated.

Figure 3.

RT-PCR analysis. a, Analysis of family 329, demonstrating the skipping of exon 7 in the CUL4B transcript. b, Analysis of family 363, showing deletion of the terminal 80 bp of exon 20, which results from the activation of a cryptic splice-donor site upstream from the normal donor site.

Figure 4.

Alignment of available CUL4B protein sequences, showing the conservation of amino acid residues altered by the missense mutations. Accession numbers in parentheses are from the Ensembl Genome Browser.

Figure 5.

a, b, and d, Three half brothers from family 42 (pedigree designations IV-1, IV-2, and IV-3, respectively), aged 21, 18, and 15 years, respectively. c, Feet of IV-2, showing a wide sandal gap and small size. e and f, Individual IV-2 from family 43, at ages 4 mo (e) and 4 years (f). g, Features of an affected cousin, IV-4. h, i, and j, Individual IV-1 from family 363 at age 6 years, showing gynecomastia (h and i), and at age 13 years, showing splayed toes with a wide sandal gap (j). k, l, and m, Uncle (III-4) of IV-1 from family 363, showing central obesity (k), upper dorsal kyphosis (l), and micropenis (m).