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Human Molecular Genetics Pages 1327-1332  

Human doublecortin (DCX) and the homologous gene in mouse encode a putative Ca2+-dependent signaling protein which is mutated in human X-linked neuronal migration defects
Introduction
Results
   LIS/SBH critical region on Xq23 and the DCX gene
   Point mutations of the DCX gene
   Expression of the DCX gene in brain
   Homologous mouse doublecortin (Dcx) gene
Discussion
Materials And Methods
   Patients, family materials and cell lines
   cDNA screening
   PCR assays and mutation searches
   Expression studies
Acknowledgements
References

Human doublecortin (DCX) and the homologous gene in mouse encode a putative Ca<sup>2+</sup>-dependent signaling protein which is mutated in human X-linked neuronal migration defects

Human doublecortin (DCX) and the homologous gene in mouse encode a putative Ca2+-dependent signaling protein which is mutated in human X-linked neuronal migration defects

Khalid Sossey-Alaoui1,+, Andrew J. Hartung1,+, Renzo Guerrini2, David K. Manchester3, Annio Posar4, A. Puche-Mira5, Eva Andermann6, William B. Dobyns7, Anand K. Srivastava1,*

1J. C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USA, 2Institute of Child Neurology and Psychiatry, University of Pisa, Pisa, Italy, 3Division of Genetics, The Children's Hospital, Denver, CO, USA, 4Department of Child Neurology and Psychiatry, Institute of Neurology, University of Bologna, Bologna, Italy, 5Hospital Universario V. Arrixaca, Murcia, Spain, 6The Neurological Institute and McGill University, Montreal, Canada and 7Department of Neurology, UMHC, Minneapolis, MN, USA

Received April 24, 1998; Accepted May 8, 1998

DDBJ/EMBL/GenBank accession nos AF040254, AF040255, AF045547

Subcortical band heterotopia (SBH) and classical lissencephaly (LIS) result from deficient neuronal migration which causes mental retardation and epilepsy. A single LIS/SBH locus on Xq22.3-q24 was mapped by linkage analysis and physical mapping of the breakpoint in an X;2 translocation. A recently identified gene, doublecortin (DCX), is expressed in fetal brain and mutated in LIS/SBH patients. We have identified four novel missense mutations in the gene, one familial mutation with LIS in a male and SBH in the carrier females, one de novo mutation in an SBH female, and two mutations in sporadic SBH female patients. The DCX gene is found to be expressed exclusively at a very high level in the adult frontal lobe. We have also cloned the X-linked mouse doublecortin (Dcx) gene. It encodes isoforms of a highly hydrophilic 40 kDa protein, homologous to its human counterpart and containing several potential phosphorylation sites. Both human and mouse DCX proteins are homologous to a CNS protein containing a Ca2+/calmodulin kinase domain, suggesting that the DCX protein may belong to a novel class of intracellular proteins involved in neuronal migration through Ca2+-dependent signaling.

INTRODUCTION

Several malformations of cortical development in human and mouse involve incomplete or defective migration of cortical neurons (1-4). Lissencephaly (LIS) or `smooth brain' represents a group of phenotypically overlapping but distinguishable disorders of cortical development and can produce epilepsy with multiple seizures, mixed hypotonia, spasticity and mental retardation (1). Classical lissencephaly consists of diffuse agyria and pachygyria with an abnormally thick cortex containing a thick zone of heterotopic neurons (Fig. 1). Subcortical band heterotopia (SBH), also known as `double cortex' (DC) and `subcortical laminar heterotopia' (SCLH), is a similar though less severe malformation exhibiting bilateral and symmetric bands of gray matter in the central white matter (Fig. 1). LIS and SBH have been observed in different regions of the same brain, and thus comprise a single agyria-pachygyria band spectrum of malformations (5,6). The SBH phenotype, diagnosed largely in females, has variable degrees of mental retardation, with some females having normal intelligence (5,6). The relative thickness of the band often correlates with the severity of mental retardation and seizures (5).

Both autosomal and X-linked forms of LIS and SBH have been described (1,7). Mutations in the 45 kDa [alpha]-subunit of the brain isoform of platelet-activating factor (PAF) acetylhydrolase cause chromosome 17-linked LIS (LIS1) (8-10). Linkage analysis in several families with LIS in affected males and SBH in carrier females (11-13) and physical mapping of a X;2 translocation breakpoint associated with LIS in a female have defined a single locus (LISX; OMIM 300067) for both LIS and SBH phenotypes on Xq22.3-q24 (12,13). The breakpoint region and the LISX critical region was narrowed further within a single yeast artificial chromosome (YAC) clone containing marker DXS287 (13). Recently a novel LISX gene, doublecortin, was cloned and shown to contain mutations in X-linked LIS/SBH patients and to be interrupted by the X;2 translocation (14,15). The LISX gene has now been renamed as `DCX' (HUGO nomenclature committee, OMIM 300121). In parallel work, we have also cloned the DCX gene (16) and report here novel mutations of the gene in four unrelated familial and sporadic patients with LIS/SBH. We have found a high level of expression of the gene in adult human frontal lobe and have cloned the mouse Dcx gene. The expression of the protein and its partial homology with other brain proteins containing Ca2+/calmodulin-dependent kinase domains suggest possible features of its function.


Figure 1. Lissencephaly and subcortical band heterotopia compared with normal brain. T1-weighted magnetic resonance images are shown. (a) A normal brain; (b) LIS in a girl (LP89-009) with a t(X;2) disrupting the DCX gene; (c) SBH in a female child (LP96-034) with a mutation R186C of the DCX gene. The arrow indicates the subcortical band.

RESULTS

LIS/SBH critical region on Xq23 and the DCX gene

Assembly of a YAC-based physical map of the LIS/SBH critical region between DXS287 and DXS1072 (17) facilitated the cloning of the human DCX gene (16). The gene is transcribed in a tel-5[prime]-3[prime]-cen direction (14-16) and spans the t(X;2) breakpoint (15 and data not shown). Several other genes and expressed sequences have been identified and mapped to the LIS/SBH region. A human homolog of the rodent PAK gene (p21-activated kinase; HPAK) was mapped centromeric to the DCX gene by Gleeson et al. (15) in a single YAC clone. We have physically mapped an expressed sequence, DXS7012E, telomeric to the DCX gene and centromeric to DXS1059 in overlapping YAC clones. An intronless gene, CRIPTO3, encoding a 188 amino acid epidermal growth factor-related protein that had been mapped tentatively to Xq21-q22 (18), is now physically mapped telomeric to DXS287 and centromeric to the translocation breakpoint. The order of the markers in the LIS/SBH region is in agreement with a previously published map (14). A detailed sequence-tagged site (STS)/YAC-based physical map of the region (data not shown) contains >26 STSs, and we have determined the order of markers cen.-DXS456-DXS6749- AFM317wb9-DXS287-CRIPTO3 (3[prime]->5[prime])-DCX-3[prime]-AFM340za9-t(X;2)DXS8204-DXS8110-DXS1059-DXS1072-tel.

Point mutations of the DCX gene

No gross molecular rearrangements were noted in 20 unrelated LIS/SBH patients in a Southern analysis with the DCX cDNA probe (data not shown). The first two coding exons (exons 2 and 3; ref. 14 and data not shown), comprising about two-thirds of the entire coding region of the DCX gene, were screened for mutations. We amplified PCR products from the genomic DNA of patients and detected single-strand conformation polymorphism (SSCP) changes in four unrelated patients. The corresponding PCR products were sequenced on both strands. All patients had single base substitutions (Fig. 2; Table 1). We confirmed co-inheritance of a sequence change (299G->C) with the phenotype in family E by sequencing corresponding PCR products from affected and carrier individuals (Fig. 2a). The mutation was hemizygous in the affected LIS male and heterozygous in his SBH mother and a SBH sister. No corresponding mutation was found in the unaffected father, sister and brother (Fig. 2a). For patient II-4 (LP94-57), a mutation has arisen de novo, because the unaffected mother does not carry the mutation identified in her SBH daughter (Fig. 2b; Table 1). The unaffected father and her normal sister showed no mutation (Fig. 2b). Two sporadic SBH females, patient 2 (Fig. 2c) and patient 3 (Fig. 2d), were heterozygous for a respective single nucleotide change (Fig. 2c and d; Table 1). The single nucleotide change generated at least one unique restriction site (Table 1). We have re-confirmed mutations by an analysis of the respective genomic fragments from affected and unaffected individuals and random control samples with an appropriate restriction endonuclease (data not shown and Table 1). None of these sequence variations was observed in an analysis of >70 X chromosomes.


Figure 2. Detection of point mutations. SSCP was performed with DNA samples of exons 2 and 3 and corresponding sequencing was performed with gel-purified fragments for the respective exons. (a) In family E (LP96-031), SSCP revealed a normal pattern in a control male and a variation in a LIS male, SBH daughter and SBH mother (data not shown). The corresponding sequence (antisense strand) of the respective fragment showing a 299C->G nucleotide change, hemizygous in LIS male (II-4) and heterozygous in SBH females (I-2 and II-3). (b) SSCP detected variation in an SBH female (II-4, LP94-057; data not shown). The corresponding sequence (sense strand) showing a heterozygous sequence variation 600C->G in SBH female (II-4) but not in unaffected parents and a sister. (c) Normal sequence in a control male (panel 1, antisense strand) and the corresponding sequence showing a heterozygous sequence variation 556G->A in a sporadic SBH female (patient 2, panel 2). (d) Normal sequence in a control male (panel 1, sense strand) and the corresponding sequence showing a heterozygous sequence variation 233G->T in a sporadic SBH female (patient 3, panel 2).

Expression of the DCX gene in brain

Northern analysis of fetal and adult human tissue blots using the human DCX cDNA (16) as a hybridization probe detected a transcript of ~9.5 kb, exclusively expressed at a very low level in adult brain (Fig. 3) and at a very high level in fetal brain (data not shown and refs 14,15). An identical transcript was also observed during mouse embryogenesis (data not shown and ref. 15). To monitor the expression pattern in the human brain, we used northern blots containing RNAs from different regions of the adult human brain. Very high expression was detected in the adult frontal lobe. A very low level of expression in other regions was detected (Fig. 3).


Figure 3. Northern blot analysis of the DCX in the human brain. Northern blots containing RNA from different human adult brain sections were hybridized to a 406 bp probe from the coding region of the DCX cDNA. A single, ~9.5 kb, transcript is present at very high level in adult frontal lobe section. Identical results were obtained with a probe from 3[prime]-non-coding region (data not shown).

Table 1. Summary of mutations in LIS/SBH patients
Patient Nucleotide change Predicted effect on protein Phenotype Altered restriction sitea
Family E (LP96-031) 299G->C Gly->Ala at 100 One LIS male, one SBH
sister and SBH mother		 +TspRI
Patient II-4 (LP94-057) 600C->G Asn->Lys at 200 SBH female, unaffected
parents without mutation		 +Eco57I
Patient 2 (LP96-034) 556C->T Arg->Cys at 186 SBH female +PstI
Patient 3 (LP94-055) 233G->T Arg->Leu at 78 SBH female +DdeI
a(+) mutation results in creation of the respective restriction site.

Homologous mouse doublecortin (Dcx) gene

Conceptual translation of the human doublecortin transcript predicted isoforms of a 40 kDa protein consisting of 360 and 365 amino acids (14-16). A partial transcript (300 bp coding sequence) in mouse indicated the presence of a homologous protein (14).

We isolated cDNA clones from a mouse embryo cDNA library screened by hybridization with a human DCX cDNA probe (16) and assembled a 1202 bp homologous mouse transcript sequence (19). The mouse transcript contains an open reading frame (ORF) of 1098 bp, with a conserved initiation site (20) and 90% identity to the coding region of the human DCX gene. An STS derived from the 5[prime] and the 3[prime] end of the mouse transcript amplified a specific fragment from a somatic cell hybrid containing the mouse X chromosome, confirming its X-chromosomal location (data not shown). Conceptual translation predicted a 365 residue mouse Dcx protein that is 99% identical to the human counterpart (Fig. 4). Interestingly, in an analogous case, mouse and human LIS1 proteins are also very highly homologous [99.8% (21)].


Figure 4. Amino acid sequence comparison of the mouse Dcx protein with its human counterpart. Identities are shown as dots. An isoform of the mouse protein contains a single amino acid `V' insertion at residue 347 (not shown). Conserved predicted phosphorylation sites for protein kinase C (#) and casein kinase II (+), and two ASN glycosylation sites (*), are marked above the sequence. Myristyl sites are underlined.

Several predicted protein kinase C (PKC) and casein kinase II (CK2) phosphorylation sites, a potential site for Ab1 at tyrosine residue 70, two potential Asn glycosylation sites and several myristylation sites were conserved in both human and mouse proteins (Fig. 4). A 34 amino acid segment at the C-terminal domain of the DCX protein (Fig. 4; amino acids 315-348) is 78% homologous to the N-terminal segment of a rat Ca2+/calmodulin-dependent kinase (22). An identical region was also present in KIAA00369, a predicted brain protein (23) that contains two distinct regions, an N-terminal 345 amino acid region homologous to the DCX protein, and a C-terminal 416 amino acid region homologous to Ca2+/calmodulin-dependent protein kinase II (22,23).

DISCUSSION

Several lines of evidence had indicated that both LIS and SBH are caused by a single gene mutation (11-13). This was confirmed by recent cloning of the doublecortin gene (now abbreviated DCX), containing mutations in LIS/SBH patients (14,15). We have also cloned the human DCX gene [originally named lissencephalin-X (LISX) (16)] as well as its mouse homolog. Our evidence supports the involvement of the DCX gene in X-linked LIS and SBH phenotypes. Point mutations in the human gene are associated with familial and sporadic LIS/SBH patients, and disruption of the gene by a translocation in a rare female patient shows classical LIS, a phenotype otherwise seen in affected hemizygous males. These observations and the finding of specific expression of the gene in the developing brain at the time when the cerebral cortex develops are consistent with its involvement in neuronal migration during the establishment of the cerebral cortex.

The strong conservation of the gene in mouse and its expression during mouse embryogenesis further strengthen its involvement in basic cortex development. Expression of the Dcx gene during mouse embryogenesis [11-17 d.p.c. (data not shown and ref. 15)] is consistent with the timing of cerebral cortex formation in mouse from about embryonic day E11, with movement of young neurons out of the ventricular zone to establish several embryonic lamina (24). As expected, no expression was detected in 7 d.p.c. mouse embryos (data not shown).

Our results further indicate a significantly higher expression of the DCX gene in the adult frontal lobe region, and suggest a possible role for neuronal migration and the DCX gene in that region of the adult brain. Recent studies have indicated adult neurogenesis in specific regions of the adult vertebrate forebrain (reviewed in ref. 25). Interestingly, in patients with less severe phenotypes, the LIS or SBH may be more severe anteriorly, with frontal pachygyria transitioning to a more normal gyral pattern posteriorly (26).

No specific region of the gene seems to be associated with severity of the LIS or SBH phenotype in patients. No predicted phosphorylation sites or other domains have been found to be altered in patients with point mutations. A mutation (R59L) was identified in an SBH female from a family with known male lethality (15). It has been suggested that this mutation may define a `critical region of the DCX gene'. However, the location of this mutation and the inferred amino acid change do not agree with the reported sequence obtained from the patient DNA (15). There is, however, a suggestion of a possible different `critical segment' of the gene. Three mutations (R186C, R192W and N200K; Table 1) were present within a 15 amino acid segment (Fig. 4; 186RSGVKPRKAVRVLLN200) and may comprise an interactive segment of the DCX protein.

Mutations producing a milder phenotype in affected females (SBH) could result from mosaicism in neurons due to random inactivation of normal and mutant X chromosomes. Inactivation studies in appropriate neuronal cells would be required to confirm this hypothesis. However, the LIS phenotype in a female with the balanced t(X;2) translocation and skewed inactivation pattern supports this notion.

The presence of several phosphorylation sites in the DCX protein is consistent with a function in a signaling pathway. The DCX protein has homology with the N-terminal half of KIAA00369, a predicted brain protein that maps to chromosome 13 (23) and contains a C-terminal 416 amino acid region homologous to several Ca2+/calmodulin-dependent protein kinases. The KIAA00369 protein homology with the DCX protein and its exclusive expression in brain further suggest a likely role for this CNS gene in the neuronal migration in the developing brain and perhaps in the adult brain (K. Sossey-Alaoui et al., in preparation). Both human and mouse DCX proteins have a short C-terminal domain that is homologous to the N-terminal segment of the rat Ca2+/calmodulin-dependent kinase (22). It has been suggested that activation of rat Ca2+/calmodulin kinase protein in brain is likely to be an important way to raise Ca2+ concentrations in neuronal tissue (27).

The phenotypic and pathological similarities between patients with mutations of the DCX gene in Xq22.3-q23 or the LIS1 gene on chromosome 17p13.3 suggest involvement of both in a common or related molecular mechanism affecting neuronal migration. For example, magnetic resonance imaging (MRI) of the brain of a girl with a X;2 translocation (Fig. 1b) showed a pattern indistinguishable from the MRI of a LIS male [X-linked or chromosome 17-linked (12,28)]. The protein product of the LIS1 gene functions, at least in part, as a regulatory subunit of the brain PAF acetylhydrolase, an enzyme that inactivates PAF. The physiological function of PAF in neuronal migration is mediated through the neuronal PAF receptor, activation of which results in increased Ca2+ mobilization in neuronal cells (29,30) and has been shown to disrupt the neuronal migration in vitro (31). Other evidence thus suggests a direct role for Ca2+ in cortical development, and intracellular fluctuations of Ca2+ specifically affect neuronal migration (32-35). Our findings further suggest that the DCX protein may play a regulatory role in Ca2+-dependent signaling that affects neuronal migration. In its absence, neuronal migration is defective, thus accounting for the associated abnormalities.

MATERIALS AND METHODS

Patients, family materials and cell lines

Patients with LIS and SBH were studied with their informed consent. Family E and a female (JF) with the t(X;2) translocation have been described earlier (12). All families and sporadic patients were ascertained as part of an ongoing Lissencephaly Research Project (36) which includes referral from two parent support organizations: the Lissencephaly Network in North America and the Lissencephaly Contact Group in the UK. Brain MRI scans of affected females and males have been analyzed by one of us (W.B.D.).

cDNA screening

Mouse cDNA clones were isolated by screening a mouse 17 day embryo 5[prime]-stretch plus cDNA library (Clontech) by hybridization with a 2284 bp human DCX cDNA clone insert (16). Several mouse cDNA clones were identified. Five cDNA clones were plaque purified. The inserts of clones were amplified with [lambda] gt11 vector primers and sequenced. Sequencing of cloned fragments and PCR products was done manually using the fmol DNA cycle sequencing system (Promega). Genomic and cDNA sequences were analyzed by BLAST and FASTA against GenBank. Sequence alignment and analyses were accomplished using the DNASTAR program (DNASTAR, Madison, WI). Other nucleotide and protein analyses were performed using the BCM search launcher (37).

PCR assays and mutation searches

PCR assays used Taq polymerase (Boehringer Mannheim) and initial denaturation at 95°C for 180 s followed by 35 cycles of 95°C for 30 s, 65°C for 30 s and 72°C for 30-60 s. Genomic DNA (25-50 ng/20 µl reaction mix) was used as template. Primers used were, for exon 2, 5[prime]-GGGTTGCCTAGCCCCACTCACAGCG and 5[prime]-ACAGAGATCGCGTCAGGTCAGCCA (202 bp PCR product), and 5[prime]-CCGCAATGGGGACCGCTACTTC and 5[prime]-CCTTCCTCCAGTTCATCCATGCT (192 bp PCR product); for exon 3, 5[prime]-CAGTGCACAGGCCAGGGAGAACAA and 5[prime]-GACAACCCCGGTCTCCAGTTTGAT (178 bp PCR product). Exons 2 and 3 of the human DCX gene were PCR amplified from the genomic DNA of patient DNAs and analyzed for SSCPs. PCR products were dephosphorylated using shrimp alkaline phosphatase (Boehringer Mannheim), heat inactivated, and 32P end-labeled using T4 polynucleotide kinase. An aliquot of the 32P-labeled product was denatured in loading buffer and analyzed on a 0.5× MDE (FMC) gel run at 6 W for 14 h at room temperature. The radioactive signal was visualized using X-Omat film (Eastman Kodak). PCR products from patients with abnormally migrating bands and appropriate control DNAs were sequenced manually (see above) on both strands. Restriction analysis was performed using standard methods (38).

Expression studies

Northern blots (Clontech) containing poly(A)+ RNAs from different human adult and fetal tissues and poly(A)+ RNAs from different human brain sections (from individuals of ages 16-75 years) were hybridized with a 406 bp DCX cDNA probe (amplified with primers 5[prime]-CCGCAATGGGGACCGCTACTTC and 5[prime]-CTTCCGAGGCTTCACCCCACTGC) or with a 798 bp non-coding 3[prime]-terminal cDNA probe (amplified with primers 5[prime]-GTCTTCCTTCTGTAGAGGGCTG and 5[prime]-CTCCTGGAGGTTACTGTTTGGCAG). Northern blots of mouse adult tissues and mouse embryos were hybridized with a 2284 bp human DCX cDNA clone insert (16). Filters were washed at high stringency according to the manufacturer's (Clontech) recommendations.

ACKNOWLEDGEMENTS

We are grateful to the family members and individuals who participated in this study. We thank M. Elizabeth Ross, W. Blackburn and R.E. Stevenson for discussions during this study; D. Schlessinger and C.E. Schwartz for valuable suggestions and critical reading of the manuscript; R. Nagaraja for sharing mapping information from the Xq24 region and P. Lalley for somatic cell hybrid DNA-containing mouse X chromosome. We also thank B. Hane, L. Jones, S.-C. Yates, S. Minnerath and S. McMillan for technical assistance. This study was supported by a grant from the National Institutes of Health (R01-NS35515; A.K.S. and W.B.D.).

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*To whom correspondence should be addressed. Tel: +1 864 388 1806; Fax: +1 864 388 1808; Email: anand@ggc.org
+These authors contributed equally to this work

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