Mutations in the gene encoding the Sigma 2 subunit of the adaptor protein 1 complex, AP1S2, cause X-linked mental retardation

Abstract

In a systematic sequencing screen of the coding exons of the X chromosome in 250 families with X-linked mental retardation (XLMR), we identified two nonsense mutations and one consensus splice-site mutation in the AP1S2 gene on Xp22 in three families. Affected individuals in these families showed mild-to-profound mental retardation. Other features included hypotonia early in life and delay in walking. AP1S2 encodes an adaptin protein that constitutes part of the adaptor protein complex found at the cytoplasmic face of coated vesicles located at the Golgi complex. The complex mediates the recruitment of clathrin to the vesicle membrane. Aberrant endocytic processing through disruption of adaptor protein complexes is likely to result from the AP1S2 mutations identified in the three XLMR-affected families, and such defects may plausibly cause abnormal synaptic development and function. AP1S2 is the first reported XLMR gene that encodes a protein directly involved in the assembly of endocytic vesicles.

Figure 1.

Pedigrees of XLMR-affected families with mutations in AP1S2. Individuals with an asterisk carry the mutant allele in each family. Symbols with a dot represent obligate female carriers. Representative electropherograms of wild type (wt) and mutant sequences are shown below each pedigree.

Figure 2.

a, Schematic representation of the exon structure of AP1S2, with positions of mutations found in XLMR-affected families. b, Schematic representation of the coding sequence. The clathrin adaptor complex small-chain functional domain is marked, and positions of mutations are indicated. The dashed arrow indicates the predicted position of the translational stop codon, under the assumption of exon 3 skipping in family 63.

Figure 3.

Photographs of the affected males in family 63. a and b, Individual II-7, aged 42 years. c and d, III-4, aged 24 years. e and f, III-1, aged 23 years. g and h, III-2, aged 11 years.

Figure 4.

RT-PCR analysis of the AP1S2 gene on lymphocyte-cell RNA in the proband from family 445 (blackened square) and a control individual (unblackened square). PCR amplification of AP1S2 and the esterase D gene (EST D) shows no difference between affected and unaffected individuals. pUC19/HpaII was used as a molecular weight marker. Experiments were performed in the presence (+) or absence (−) of reverse transcriptase. gDNA = genomic DNA.