Human Molecular Genetics, 2002, Vol. 11, No. 15 1757-1762
© 2002 Oxford University Press
A common protein interaction domain links two recently identified epilepsy genes
Bioinformatics Group, MEMOREC Stoffel GmbH, Stöckheimer Weg 1, D-50829 Köln, Germany
Received April 8, 2002; Accepted May 27, 2002
DDBJ/EMBL/GenBank accession nos AJ487958–AJ487962
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Until recently, all genes found to be mutated in hereditary idiopathic epilepsies encoded subunits of ion channels, leading to the view of this class of diseases as channelopathies. Two apparent exceptions to this rule are the MASS1 gene, which is mutated in the Frings mouse model of audiogenic epilepsy, and the LGI1 gene, which is mutated in autosomal dominant partial epilepsy with auditory features (ADPEAF). Careful sequence analysis of the two protein products encoded by those genes shows a common feature: both sequences harbour a novel homology domain consisting of a 7-fold repeated 44-residue motif. The architecture and structural features of this new domain make it a likely member of the growing class of protein interaction domains with a seven-bladed ß-propeller fold. In the MASS1 gene product, which has recently been shown to be a fragment of the very large G-protein-coupled receptor VLGR1, this EAR domain (for epilepsy-associated repeat) is part of the ligand-binding ectodomain. LGI1, as well as a number of newly identified LGI1 relatives, is predicted to be a secreted protein, and consists of an N-terminal leucine-rich repeat region and a C-terminal EAR region. The known portion of the human genome encodes six EAR proteins, some of which map to chromosome regions associated with seizure disorders. The EAR domain is likely to play an important role in the pathogenesis of epilepsy, either by binding to an unknown anti-epileptic ligand, or more likely by interfering with axon guidance or synaptogenesis.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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When a gene defect is found to be associated with a particular disease phenotype, it frequently remains a challenging task for molecular medicine to elucidate the chain of events leading from molecular to organismal pathology. In some cases, including many metabolic diseases, the connection can be quite direct: the loss of an enzymatic activity either leads to a deficit of a needed metabolite or to a toxic accumulation of a substrate. In many other pathologies, including most neurological diseases, the connection between genotype and phenotype is far from being obvious. Frequently, insights into the mechanism of a disease can be obtained from analysing multiple gene defects leading to identical or similar symptoms. Occasionally, the sequences of the affected gene products, in combination with knowledge of the mutational spectrum, can give a first clue. As an example, most spinocerebellar ataxias (SCA) are caused by mutations in genes encoding proteins with extended polyglutamine tracts showing repeat-length instability (1). It is this common feature of the SCA genes that is crucial for the ataxia disease to arise, by a mechanism that is not entirely understood. In other cases, the connection between the causative genes is their participation in a common pathway – a property that cannot be derived easily from the sequences alone. Examples include familial Alzheimer's disease (FAD), where one gene product (presenilin) is a protease required for the processing of another gene product (APP) (2), and Parkinson's disease, where one gene product (parkin) is involved in the ubiquitination of another gene product (synuclein) (3).
Until recently, the idiopathic epilepsies, i.e. the hereditary forms of epilepsy that are not just symptoms of another underlying disease or malformation, all shared one common defining feature: the causative genes all turned out to encode subunits of ion channels expressed in the brain. Although there is considerable variation in the class of ion channels involved, including voltage-gated sodium or potassium channels as well as acetylcholine and GABA receptors, a classification of idiopathic epilepsies as channelopathies appeared to be warranted (4–6).
This view was recently challenged by two reports describing mutations in idiopathic epilepsies that affect uncharacterized proteins with no obvious connections to ion channels. The Frings mouse is a monogenic animal model for an epilepsy evoked by auditory stimuli. By positional cloning and candidate gene analysis, Louis Ptacek’s group (7) succeeded in identifying the underlying mutation in a novel gene termed MASS1. The protein product of MASS1 is a large protein with multiple Calx-ß repeats, which was recently found to be a fragment of an even larger protein belonging to the class of G-protein-coupled receptors (8). The complete protein, called VLGR1, comprises no less than 6307 amino acids and is probably the largest membrane protein. The fragment originally identified as the MASS1 gene product spans the N-terminal part of the putative ligand-binding ectodomain. Recently, another seizure disorder, called ‘autosomal dominant partial epilepsy with auditory features’ (ADPEAF, EPT), was reported to be due to mutations in the LGI1 gene (9,10). LGI1 had been identified before in a different context—the loss of both LGI1 alleles appears to be a frequent finding in high-grade gliomas (11). Little is known about the function of the LGI1 gene product, which carries as the only recognizable sequence feature an N-terminal signal sequence and a number of leucine-rich repeats (LRRs) in the N-terminal half of the protein.
An exhaustive sequence analysis of VLGR1/MASS1 and LGI1, using the generalized profile method for sensitive protein comparisons (12), was able to uncover a novel sequence feature shared by both proteins. The presence of a common functional domain in the two known non-channel epilepsy genes suggests an alternative pathway contributing to the epileptic phenotype.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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VLGR1/MASS1 belongs to the superfamily of seven-helix G-protein-coupled receptors and, more specifically, to the secretin-receptor-like subfamily. A particular subset of this receptor class is characterized by a very long extracellular domain, carrying an N-terminal signal peptide and a C-terminal GPS domain, which is thought to contain a conserved protease cleavage site (13). Typical members belonging to this subset, such as the latrophilins and the flamingo-like receptors, contain in their ectodomain a large number of recognizable homology domains, which probably play a role in ligand binding. As described in the original report on VLGR1 (8), the predominant domain type found in that protein is the Calx-ß domain (14,15). By using the generalized profile method, 37 copies of the Calx domain could be detected (Fig. 1). In one of the few regions devoid of Calx domains resides another homology region, which shares significant sequence relationship to several domain types known to be related (16): the LamG domain, the TSP-N domain, and the pentraxin domain.
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An interesting finding emerged from the initial observation of a moderately well conserved 46-residue tandem repeat in the sequence region 3250–3550 of VLGR1, embedded within two halves of a split Calx-ß domain. The construction of a generalized profile from this repeat region revealed the existence of further repeat copies at both flanks of the initial region. By iterative profile refinement (17), six adjacent repeat copies were detected in the VLGR1/MASS1 protein sequences of both human and murine origin. In this process, the original repeat period had to be shortened to approximately 42–44 residues in order to avoid overlapping of adjacent copies (Fig. 2). In addition to VLGR1/MASS1, three other sequences in the protein database were found to contain a similar repeat region. One of these proteins is the LGI1 gene product, which was recently found to be mutated in ADPEAF epilepsy. VLGR1/MASS1 and LGI1 are the only characterized proteins harbouring the new repeat. As both proteins are involved in epilepsy pathologies, we refer to the new repeat as the EAR (for epilepsy-associated repeat) domain.
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The third sequence containing the EAR domain is KIAA1916, a protein closely related to LGI1. In both proteins, seven adjacent copies of the repeat could be detected in the C-terminal region. The N-terminal half consists of four copies of the LRR, surrounded by two flanking regions frequently found to be associated with extracellular LRRs. There are contradicting predictions of the presence or absence of a putative membrane-spanning region in the LGI1 protein (10,11). Our analysis did not reveal a sequence stretch of sufficient hydrophobicity to span a membrane bilayer. Moreover, the hydrophobic patch found in LGI1 is not found in the other copies of the EAR repeat. We thus predict LGI1 and KIAA1916 to be secreted proteins. A fourth EAR protein, an anonymous database entry (GenBank Accession no. BC021197), is characterized by the presence of an N-terminal thrombospondin-N domain (TSP-N). Based on the analysis of EST sequences from various organisms, also taking into account the corresponding genomic database entries, we predict that the BC021197 database entry is incomplete. A longer sequence, which we call TSPEAR to reflect the domain structure, has been deposited in the database and contains seven adjacent copies of the EAR repeat.
Since the two characterized EAR proteins are both involved in epilepsy, it is tempting to speculate that other uncharacterized EAR proteins are also involved in related processes. In order to identify the whole complement of human EAR proteins, we also performed profile searches in EST databases and genome databases. We were able to identify two more members of the EAR family, both of which are close relatives of LGI1. Apparently, LGI1 is a member of a small family comprising four human proteins. All new members of this family, including an extended version of the KIAA1916 sequence, have been deposited in the database, where they are referred to as LGIL2 (KIA1916), LGIL3 and LGIL4. The domain architecture of the six human EAR proteins is depicted in Figure 1, while a multiple alignment of their EAR copies is shown in Figure 2. Recently, this LGI1-like protein family has also been published by others (18).
In order to assess the status of the EAR-containing gene products as candidates for further seizure disorders, we determined their chromosomal location from the human genome data via BLAST searches in the Ensembl database (19) (Table 1). The Ensembl assignments were confirmed by experimentally obtained chromosomal mapping for several genes found adjacent on the respective PAC clones. The adjacency to the BMP1 gene was used for the localization of LGIL4, which is not yet present in the Ensembl database. The expression pattern can be considered an additional criterion in assessing a putative involvement in epilepsy. For two of the newly identified genes, a clear expression preference for brain was detected by analyzing EST frequencies and SAGE tag counts from public sources (20) (Table 1).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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A number of observations suggest that the EAR domain is a novel member of the growing family of ß-propeller domains: (i) the repeat has a periodicity of approximately 44 residues; (ii) the secondary structure prediction for the EAR repeat, using the PHD server, yields an arrangement of four short ß-strands interrupted by non-structured regions; (iii) the complete domain apparently consist of seven repeat copies. All three properties are hallmarks of several domains known to belong to the ß-propeller fold (21), including WD repeats, Kelch repeats, the clathrin head domain and many others. Members of this fold are found both in intracellular and in secreted proteins. A common functional element found in all characterized domains of this class is a participation in protein–protein interactions, whereas the nature of the bound protein can vary widely. Since the EAR repeat is found in the ectodomain of VLGR1, it is most probably involved in ligand recognition by the receptor.
In contrast to the WD repeats, there are no highly conserved or even invariant positions in the EAR repeat. Thus, an enzymatic role for the domain is highly unlikely. The disease mutation in VLGR1/MASS1, as well as most of the mutations found in LGI1, lead to premature stop codons and result in truncated gene products (7,9). In one family, an ADPEAF-associated missense mutation is observed in the LGI1 gene. The affected amino acid is Glu383, which is mutated to an Ala residue. Interestingly, Glu383, which is localized in the second ß strand of the fourth EAR copy, is conserved in LGIL2, 3 and 4 (Figure 2). A glutamate residue at a corresponding position in the third EAR copy is also invariant in the entire LGI1 family. In VLGR1/MASS1, the repeat copies 2 and 5 contain a glutamate at this position, while in TSPEAR, a corresponding glutamate is found in all repeat copies except for the second one. It is likely that this position is important either for ligand binding or for maintaining structural integrity.
As shown in Table 1, the chromosomal loci of the EAR-containing genes were analysed for their possible correspondence with mapped disease regions in OMIM (22) and the literature. In particular the EAR-containing genes with a predominant expression in brain would appear good candidates for additional epilepsy genes. No epilepsy or related seizure disorder has been assigned to the 4p15.31 region harbouring the LGIL2 gene. By contrast, the 19q13.12 region, where the brain-enriched LGIL3 is located, has been associated with two different forms of hereditary epilepsy. One of them, a form of ‘generalized epilepsy with febrile seizures plus’ (GEFS+), has been shown to be due to a mutation in the sodium channel subunit SCN1B in at least one family (23). The LGIL3 gene maps remarkably close to SCN1B within an interval of 60 kb. A second epilepsy phenotype mapped to 19q12–13.1 is known as ‘benign familial infantile convulsions’ (BFIC) (24). This rare autosomal dominant disease does not seem to be caused by mutations in SCN1B (25), and LGIL3 might be considered a candidate gene for this condition. For LGIL4 and TSPEAR, no convincing linkages to causally unclear epileptic conditions were found. LGIL4 maps to 8p21.2 within the relatively large critical region for torsion dystonia 6 (DYT6) at 8p21–q22, but is not particularly close to the marker showing maximum linkage. TSPEAR is localized at 21q22.3, at a short distance (600 kb) from cystatin B, the gene mutated in Unverricht–Lundborg-type progressive myoclonus epilepsy (EPM1). Based on current knowledge, only the LGI1-like LGIL3 can be considered a candidate gene for epilepsy. This idea is corroborated by the dominant inheritance mode of BFIC, which is also observed in ADPEAF, and by the very similar expression patterns of LGI1 and LGIL3 as judged by SAGE data (not shown).
The remaining questions of crucial importance concern the function of the VLGR1/MASS1 and LGI1 gene products, the specific role of the EAR domain within those proteins, and finally the disease mechanism. It is obvious that experiments are required to properly address those issues. Nevertheless, some clues can be obtained from sequence analysis. Of particular interest is a hypothesis already put forward in the original reports on MASS1, VLGR1 and LGI1 (7,8,11), as well as in some accompanying mini-reviews (26,27). According to this idea, VLGR1/MASS1 and LGI1 are not involved in regulating ion conductance but rather in neurogenesis, including axon guidance and synaptogenesis. It is well known that perturbations in related processes can lead to epilepsies, as exemplified by several lissencephalies and cortical band heterotopias (28), although those conditions lead to major developmental abnormalities, which also cause a number of other symptoms. It is conceivable that an increase in excitatory synapses, or a lack of functional inhibitory synapses, can also contribute to seizure disorders. A number of observations provide circumstantial evidence for a role of EAR proteins in neural development. Firstly, the message of VLGR1 is most prominent in the developing nervous system, with very little expression found in adult tissues (8). Secondly, the overall VLGR1 architecture shows considerable resemblance to other very long G-protein-coupled receptors, including the flamingo family, the latrophilins and the brain angiogenesis inhibitors. A common feature of those proteins is a role in neural development. Thirdly, the LRR domain of LGI1 is relatively closely related to the LRRs found in the neurogenic protein ‘slit’, which plays a role in axonal guidance. Finally, two proteins predicted from the Drosophila genome show a distant sequence relationship to singular EAR copies, which do not appear to cluster into groups of seven. While the functional significance of this similarity is not clear, one of those Drosophila proteins (CG11411) was recently found in a screen for axon guidance and synaptogenesis mutants (29), providing a further link between EAR proteins and developmental processes.
The structural features of the EAR domain and its occurrence in the ectodomain of a receptor suggest a role in ligand binding. Unfortunately, it is not possible to predict the nature of the ligand from the sequence of the EAR domain alone. The fact that at least two EAR proteins are involved in epilepsies, while the other proteins are uncharacterized, makes it tempting to speculate that the EAR domains in VLGR1/MASS1 and LGI1 bind to the same ligand or at least to functionally related ligands. A further possibility, which cannot be excluded, is a direct interaction between the VLGR1/MASS1 and LGI1 gene products. It is interesting to note that all disease-causing mutations in VLGR1/MASS1 and LGI1 are either truncations leading to a complete loss of the EAR domain or missense mutations at a conserved position of the EAR repeat, possibly rendering the domain unstable or functionally inactive.
The mutation in VLGR1/MASS1 results in a dramatically truncated protein lacking not only the EAR domain but also the entire membrane-spanning region. The expected loss of receptor function in this allele can easily be reconciled with the observed recessive mode of inheritance. On the other hand, the LGI1 mutations are inherited in a dominant fashion, and haploinsufficiency had been proposed as the likely explanation (9). It should be noted that proteins with two independent interaction domains are frequently prone to gain-of-function phenotypes, arising through the dominant-negative effect of a mutated protein that has lost one of the interaction modes. All ADPEAF mutations found in LGI1, except for the 1639insA mutation, affect the EAR domain but leave the LRR domain intact. The resulting mutant protein could compete with the wild-type allele for the LRR binding partner and thus exacerbate any haploinsufficiency effect.
This question, as well as the other important issues discussed above, are likely to be addressed in future experimental studies. In particular, the identification of the EAR ligands of VLGR1/MASS1 and LGI1 will be important steps in the elucidation of the disease mechanism of idiopathic epilepsies that are not caused by ion-channel mutations.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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All database searches were performed with a non-redundant data set constructed from current releases of SwissProt, TrEMBL and GenPept (30,31). Generalized profile (12) construction and searches were run locally using the pftools package, version 2.1 (program available from the URL ftp://ftp.isrec.isb-sib.ch/sib-isrec/pftools/). Profiles were constructed using the BLOSUM45 substitution matrix (32) and default penalties of 2.1 for gap opening and 0.2 for gap extension. The statistical significance of profile matches was derived from the analysis of the score distribution of a randomized database as described previously (17,33). Database randomization was performed by individually inverting each protein sequence, using SwissProt 34 as the data source. Only sequence matches found with a probability of P<0.01 were included in subsequent rounds of iterative profile refinement. As discussed in (17), the probability values obtained by randomization scaling of profiles are much more reliable than those obtained from theoretical scaling methods using assumptions of uniformity of sequence composition. Sequences were assembled from EST and genomic data provided by the NCBI and the Ensembl project (19). Secondary structures were predicted using the PHD network server (34) using multiple alignments as queries.
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FOOTNOTES |
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* To whom correspondence should be addressed. Tel: +49 221950480; Fax: +49 2219504848; Email: kay.hofmann{at}memorec.com
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