Isolation of a novel gene from the DiGeorge syndrome critical region with homology to Drosophilagdl and to human LAMC1 genes
Isolation of a novel gene from the DiGeorge syndrome critical region with homology to Drosophila gdl and to human LAMC1 genes Suzanne Demczuk*, Gilles Thomas and Alain Aurias
INSERM U434, Institut Curie, Section de Recherche, 26 rue d'Ulm, 75231, Paris Cedex 05, France
Received December 26, 1995;Revised and Accepted February 26, 1996GenBank accession no. X96484
DiGeorge syndrome, and more widely the CATCH 22 syndrome, are associated with microdeletions in chromosomal region 22q11.2. A critical region of 500 kb has been delimited within which maps the breakpoint of a balanced translocation associated with mild CATCH 22 phenotypes. We report the isolation from this critical region of a novel gene, DGCR6, which maps 115 kb centromeric to the balanced translocation breakpoint. The DGCR6 gene product shares homology with the Drosophila melanogaster gonadal protein, which participates in gonadal and germ-line cells development, and with the human laminin [gamma]-1 chain, which upon polymerization with [alpha]- and [beta]- chains forms the laminin molecule. Laminin binds to cells through interaction with a receptor and has functions in cell attachment, migration and tissue organization during development. DGCR6 could be a candidate for involvement in the DiGeorge syndrome pathology by playing a role in neural crest cell migration into the third and fourth pharyngeal pouches, the structures from which derive the organs affected in DiGeorge syndrome.
DiGeorge syndrome (DGS) is a developmental defect which associates thymus hypo-/aplasia, parathyroids hypo-/aplasia, a conotruncal heart defect and a typical facial dysmorphism (1 ). Genetically, this syndrome is associated with microdeletions of chromosomal region 22q11.2, either through unbalanced translocations or, in the majority of cases, through interstitial deletions detectable by molecular techniques (reviewed in 2 ). Deletions of the same extent have been reported in syndromes with a phenotypic overlap to DGS, such as the Velo-Cardio-Facial syndrome (VCFS), the Conotruncal Anomaly Face syndrome and in some cases of isolated conotruncal cardiac defect either of a sporadic or familial type (3 -11 ). These findings give some indication of the wide phenotypic variability associated with 22q11.2 deletions. In fact, it has been estimated from preliminary data, that the minimum prevalence of these deletions would be 1/4000 and that deletions of 22q11.2 would be the genetic etiology in at least 5% of newborns with a heart defect (12 ).
In most instances, the deletion in DGS patients is very large (2-3 Mb long) and does not allow the delimitation of a shortest region of overlap for these syndromes (13 ). Nevertheless, affected individuals bearing unbalanced translocations have permitted the narrowing down of a critical region of at least 450 kb by ordering translocation breakpoints with respect to loci. The DiGeorge syndrome critical region (DGCR) extends from locus pH11 (D22S36) to the breakpoint of the GM00980 cell line [karyotype: 45, XX, -11, -22, +der(11), t(11;22) (q25;q11)] associated with a VCFS phenotype (14 ). It is noteworthy that the breakpoint of a balanced translocation found in a daughter and her mother (designated as ADU and VDU respectively), both affected with mild DGS, maps within this critical region (15 ). This suggests that the translocation breakpoint interrupts the major DGS gene. In a few instances, DGS patients with a very characteristic phenotype do not carry the large 22q11.2 deletion.
Up to now, three genes have been isolated from the critical region: HIRA/TupleI (DGCR1), DGCR2/IDD and human CTP (DGCR5) (16 -20 ). In addition, two potential open reading frames (DGCR3 and DGCR4) spanning the balanced translocation breakpoint have been reported (21 ).
We have previously reported the cloning of the ADU/VDU balanced translocation breakpoint by chromosome walking through the establishment of a cosmid contig (18 ). Furthermore, a novel gene (DGCR2/IDD) mapping telomeric to the breakpoint has been isolated. However, this gene is not interrupted by the balanced translocation breakpoint, and does not display any rearrangements in DGS patients which do not bear the large deletion (19 and our unpublished data). In our attempt to isolate a gene interrupted by the ADU breakpoint, we have searched for phylogenetically conserved sequences within the cosmid contig. Here, we report the cloning and characterization of a novel gene, isolated using a cosmid subfragment conserved in rodent DNA. This gene, designated DGCR6 for DGS critical region gene 6, maps 115 kb centromeric to the balanced translocation breakpoint, and is deleted in 4/4 DGS patients tested. DGCR6 was entirely sequenced and has a region of homology to the Drosophila gonadal protein and to the laminin [gamma]-1 (LAMC1) chain. Although it is not interrupted by the ADU breakpoint and no rearrangements have been elucidated in DGS patients not bearing the large deletion, the DGCR6 gene could still be a candidate for involvement in the pathology.
The 3F4 cosmid contig which encompasses the ADU balanced translocation breakpoint has been previously reported (18 ) and an updated version is depicted in Figure 1 . While performing the chromosome walk, it was noted that a 9.5 kb EcoRI fragment gave positive hybridization signals with rodent DNA, even at high wash stringency (0.1* SSC/0.1% SDS, 65oC). In our attempt to isolate genes from the DGCR in the vicinity of the ADU translocation breakpoint, we became interested in this phylogenetically conserved sequence as it could correspond to a potential gene and map to the region of interest. This 9.5 kb EcoRI band was subcloned and the interspecies-conserved sequence was narrowed down to a 300 bp ApaI subfragment, which maps about 120 kb centromeric to the ADU breakpoint (Fig. 1 ).
The 300 bp ApaI cosmid subfragment was used to screen a human Hela cell cDNA library. Several positive clones were retrieved and found to overlap by restriction mapping. The direction of transcription was found to be from centromere to telomere by hybridization, on Southern blots made of different restriction digests of the cosmids, and sequencing, of both extremities of the cDNA clones. Hybridization of the DGCR6 cDNAs to a chromosome 22-enriched cosmid library shows that the cDNA hybridizes to cosmids 39A and 126E, and spans at least 31 kb of genomic DNA. In addition, the DGCR6 cDNA maps back to the expected region of our chromosome 22 hybrid panel (22 ). Finally, cosmid 39A was hybridized by FISH on chromosome preparations of DGS patients already shown to carry the large chromosome 22 deletion. Haploinsufficiency for this cosmid locus was found in 4/4 patients tested (data not shown).
The DGCR6 gene recognizes a 1.1 kb transcript upon hybridization to poly(A)+ RNA Northern blots made of different human adult tissues (Fig. 2 ). Expression is found in all tissues examined, except placenta, and is highest in adult heart and skeletal muscle. A transcript within the same size range is found by hybridization to a Northern blot made from total RNA extracted from the Hela cell line (data not shown).
A search in nucleotide databases indicated that the sequence between nucleotides position 510 to 810 correspond to the expressed sequence tag yd38d10.r1 (GenBank accession number T82991) which has been isolated from fetal liver and fetal spleen cDNA libraries.
The predicted protein has a molecular weight of 9.1 kDa and is mostly hydrophobic. It is particularly leucine-rich. FASTA searches of the databases with the amino acid sequence revealed an homology between the N-terminal end of DGCR6and a region of the Drosophila melanogaster gonadal protein as well as a region of domain I of the human laminin [gamma]-1 chain (Fig. 4 ) (24 -26 ).
We report the isolation of a novel gene, DGCR6, from the DGCR. This gene encodes a putative protein which has an homology to the Drosophila gonadal protein and to human laminin [gamma]-1 chain. It could be a potential candidate for DGS, inasmuch as it is hemizygously deleted in all DGS patients tested in this study. However, the 3' end of DGCR6 maps 115 kb centromeric to the ADU balanced translocation breakpoint, and therefore, is not interrupted by the breakpoint. In addition, DGCR6 maps 220 kb from the proximal border of the deletion of a CATCH22 patient (patient G) with a less centromeric extent of deletion than usually seen in DGS (29 ). Nevertheless, these facts do not constitute negative arguments for the direct involvement of DGCR6 in DGS, as position effects of translocation breakpoints on genes associated with pathologies have been described for genes mapped as far as 150 kb from the rearrangement (30 -32 ).
Few data exist on the exact function of the Drosophila gonadalprotein. All that is known is that it participates in proper gonadal and germ-line cell development. No homologies with known genes or functional protein domains have been reported for gdl (24 ).
On the other hand, laminin is a well-studied protein with functions, among others, in tissue assembly, cell migration and attachment and differentiation. It is the first basement membrane protein to be expressed, as early as the 2-4 cell stage, in mouse embryos (28 ). The structure of laminin is conserved between species as remote one from the other as Drosophila and human (27 ). Laminin is considered as a mosaic protein, i.e. it is composed of a number of structurally and functionally autonomous domains found in different proteins, which are thought to have arisen by `exon shuffling' (28 ).
Furthermore, laminin [gamma]-1 has been suggested to be involved in a human pathology: a possible linkage between junctional epidermolysis bullosa inversa (MIM 226450) and a trinucleotide repeat marker in intron 20 of the laminin [gamma]-1 gene has been reported (33 ).
In DGS, the defective developmental field is the population of cephalic neural crest cells that migrates into the third and fourth pharyngeal pouches to give rise to the structures affected (great vessels of the heart, thymus, parathyroids) (1 ). Accumulating evidence suggest that the defect may be attributed to failure to attain a critical number of neural crest cells (34 -36 ). The homology between DGCR6 and laminin [gamma]-1 is in the C-terminal end of the latter. It is noteworthy that this region of laminin [gamma]-1 gives rise to a proteolytic fragment called E8, which has been shown in vitro to contain the binding site for avian neural crest cell attachment and migration (37 ). Therefore, the DGCR6 gene could be a candidate for involvement in the pathology.
Three other genes have been isolated from the DGCR and presented as candidate genes. The human mitochondrial citrate transporter gene (human CTP, DGCR5) has been mapped between the ADU and the GM00980 breakpoints (20 ). This gene does not seem to map within the two cosmid contigs constructed by us (Fig. 1 and Lorain et al., submitted), and therefore should localize at least 350 kb telomeric to the ADU breakpoint. Moreover, it is recognized that a 50% reduction in dosage of this gene is unlikely to play a major role in the development of the DGS pathology, but could be causally related to the mental deficiency reported in a proportion of DGS.
The HIRA/TUPLEI gene maps at least 180 kbtelomeric from the ADU breakpoint and shares a significant homology to repressors of core histone gene transcription in Saccharomyces cerevisiae (16 ,17 ). This gene is considered as a candidate for DGS because of a possible role as transcriptional regulator, expression in the neural tube rhombomeres in mouse and chick embryos and deletion in patient G (29 ). Involvement in the pathology of the ADU patient is suggested to be through a position effect.
The DGCR2/IDD gene maps 10 kb telomeric to the ADU breakpoint and encodes a potential adhesion receptor protein (18 ,19 ). This gene is considered a candidate for the disease because of its close proximity to the ADU breakpoint, possible involvement of the protein in adhesive interactions between cells and expression during mouse development (38 ). However, no point mutations have been found in the five DGS patients tested, which were not bearing the large deletion (19 ) .
In conclusion, no definitive arguments have been provided up to now, to make any of the genes isolated from the DGCR a better candidate for direct involvement in the DGS pathology than the others. Recently, two potential open reading frames (DGCR3 and DGCR4) physically interrupted by the ADU breakpoint have been reported and further isolation of complete cDNAs is pending (21 ). The corresponding putative genes will also represent good candidates for DGS. A few patients with a well characterized DGS phenotype exists, that do not show the large 22q11.2 deletion. These patients will be pivotal in confirming involvement of a particular gene in the pathology.
The chromosome 22-enriched genomic cosmid libraries, LL22NC01 and LL22NC03, have been prepared at the Lawrence Livermore National Laboratory (Livermore, CA). Together, these libraries cover eight genome-equivalents and have been gridded in 96-well microtitration plates. The Hela cell cDNA library cloned in the [lambda]ZAPII vector (cloning sites EcoRI) was obtained from Stratagene (LaJolla, CA). It was plated and screened according to the manufacturer's protocol. Altogether, 600 000 clones were screened. The positive clones were taken to tertiary screen and subcloned in plasmids using the [lambda]ZAPII plasmid rescue procedure according to the manufacturer's specifications.
Multiple human adult tissues Northern blots were purchased from Clontech (Palo Alto, CA) and were probed according to manufacturer's instructions. RNA was extracted from different cell lines using the phenol/guanidine isothiocyanate methodology, migrated on a 1% agarose/ 15% formaldehyde gel and transferred by the capillary method on Hybond N+ nylon membrane.
DNA was extracted from cosmids by the alkaline lysis procedure, from cultured human cell lines and from blood samples of human, rat and mouse, digested with restriction enzymes, migrated on a 0.8% agarose gel and transferred on Hybond N+ nylon membrane. Hybridizations were performed at 50oC in hybridization buffer (50% formamide, 1% SDS, 1M NaCl, 0.05 M Tris-HCl pH 7, 0.1% Na4P2O7, 10 H2O, 2 g/l Ficoll, 2 g/l polyvinylpyrrolidone, 2 g/l bovine serum albumin, 50 g/l dextran sulphate, 100 mg/ml salmon sperm DNA). Washes were in 1* SSC/0.1% SDS at 60oC for `zoo blots' and in 0.1* SSC/0.1% SDS at 65oC for human and cosmid genomic blots. If an autoradiographic band on mouse or rat DNA was visible, the blots were rewashed at increasing stringency.
The cDNA clones were sequenced by primer walking using the dideoxy chain terminator method on an Applied Biosystem ABI 373A fluorescent sequencer. Assembly of DNA sequences was performed using the computer program `Autoassembler' (Applied Biosystems, Branchburg, NJ). The sequences were used to search the Swissprot and Genbank databases using the FASTA program, available on the BISANCE server (CITI 2, Paris, France).
This work has been supported with grants from the Groupement de Recherche et d'Etudes sur les Génomes (GIP-GREG), from the Association Française contre les Myopathies (AFM) and from the European Community. S.D. is the recipient of fellowships from the Fonds pour la Formation des Chercheurs et l'Aide à la Recherche and from the Société de Secours des Amis des Sciences.
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The nucleotide sequence data reported in this paper will appear in the EMBL and GenBank Nucleotide Sequence Database under the accession number X96484 HSDGCR2.
*To whom correspondence should be addressed
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