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. 2006 Sep 12:7:28.
doi: 10.1186/1471-2199-7-28.

The human ortholog of the rodent testis-specific ABC transporter Abca17 is a ubiquitously expressed pseudogene (ABCA17P) and shares a common 5' end with ABCA3

Armin P Piehler  1 , Jürgen J Wenzel, Ole K Olstad, Kari Bente Foss Haug, Peter Kierulf, Wolfgang E Kaminski
Affiliations

The human ortholog of the rodent testis-specific ABC transporter Abca17 is a ubiquitously expressed pseudogene (ABCA17P) and shares a common 5' end with ABCA3

Armin P Piehler et al. BMC Mol Biol. .

Abstract

Background: During the past years, we and others discovered a series of human ATP-binding cassette (ABC) transporters, now referred to as ABC A-subfamily transporters. Recently, a novel testis-specific ABC A transporter, Abca17, has been cloned in rodent. In this study, we report the identification and characterization of the human ortholog of rodent Abca17.

Results: The novel human ABC A-transporter gene on chromosome 16p13.3 is ubiquitously expressed with highest expression in glandular tissues and the heart. The new ABC transporter gene exhibits striking nucleotide sequence homology with the recently cloned mouse (58%) and rat Abca17 (51%), respectively, and is located in the syntenic region of mouse Abca17 indicating that it represents the human ortholog of rodent Abca17. However, unlike in the mouse, the full-length ABCA17 transcript (4.3 kb) contains numerous mutations that preclude its translation into a bona fide ABC transporter protein strongly suggesting that the human ABCA17 gene is a transcribed pseudogene (ABCA17P). We identified numerous alternative ABCA17P splice variants which are transcribed from two distinct transcription initiation sites. Genomic analysis revealed that ABCA17P borders on another ABC A-subfamily transporter - the lung surfactant deficiency gene ABCA3. Surprisingly, we found that both genes overlap at their first exons and are transcribed from opposite strands. This genomic colocalization and the observation that the ABCA17P and ABCA3 genes share significant homologies in several exons (up to 98%) suggest that both genes have evolved by gene duplication.

Conclusion: Our results demonstrate that ABCA17P and ABCA3 form a complex of overlapping genes in the human genome from which both non-coding and protein-coding ABC A-transporter RNAs are expressed. The fact that both genes overlap at their 5' ends suggests interdependencies in their regulation and may have important implications for the functional analysis of the disease gene ABCA3. Moreover, this is the first demonstration of the expression of a pseudogene and its parent gene from a common overlapping DNA region in the human genome.

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Figures

Figure 1
Figure 1
Hypothetical amino acid sequence of human ABCA17P aligned with its murine ortholog Abca17. The ABCA17P amino acid sequence shown is derived from cDNA segments with open reading frames. Gaps due to optimal alignment are represented by dashes and asterisks (red shaded) represent premature stop codons. Green and yellow shaded amino acids highlight sequence identities and similarities, respectively. Walker A and B motifs and signature sequences, integral components of the nucleotide binding domains of ABC transporters, are black shaded. The complete cDNA sequence of the ABCA17P full-length transcript has been deposited in the NCBI GenBank [GenBank:DQ266102].
Figure 2
Figure 2
(A) Structural organization of the human ABCA17P/ABCA3 gene locus on chromosome 16p13.3. Both genes are organized in head-to-head orientation on opposite strands and overlap at their 5' ends. Exons are represented by black (ABCA17P) and gray boxes (ABCA3), respectively, and numbered in 5' to 3' order. Numbers in parentheses refer to ABCA3 exons that share >70% sequence homology with the ABCA17P exons indicated. The yellow box highlights the alternative exon 1b of the ABCA17P gene. The green box represents a common CpG island at the 5' end of both genes. A metric scale bar is shown. (B) Comparison of the human and mouse ABCA17 – ABCA3 gene borders. Shown are the first two exons of both genes and arrows indicate the respective directions of transcription. Note that the human ABCA17P and ABCA3 genes share a 1.2 kb overlap (brown box), whereas the murine Abca17 and Abca3 orthologs are separated by a 1.0 kb intergene region (blue box). An arrow identifies the novel exon 1 of the murine Abca17 gene. A metric scale bare is shown at the bottom. (C) Synopsis of alternative ABCA17P transcripts identified in this study. Shown are 20 ABCA17P transcript variants which are generated by alternative splicing of exons 2, 3, 9, 10 and a segment of exon 11 (red box), respectively. Boxes represent exons; the alternative first exon 1b is depicted by a yellow box.
Figure 3
Figure 3
Discrete regions of the ABCA17P gene show near perfect sequence identity with corresponding segments of the ABCA3 gene. This is exemplified for ABCA17P exon 15 (+ partial intron 15) and ABCA3 exon 31 (+ partial intron 31), respectively. Bold capital letters represent exon and small letters intron sequences. Red shaded nucleotides indicate known mutation sites in the ABCA3 gene in individuals with neonatal surfactant deficiency. Yellow shaded letters denote non-identical nucleotides.
Figure 4
Figure 4
Northern blot analysis of ABCA17P in various human tissues. Northern blot demonstrating robust expression of the ABCA17P full-length transcript (arrow) in a variety of human tissues. A size marker is indicated for orientation.
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