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Human Molecular GeneticsPages 317-324 © 1997 Oxford University Press
A transcript map of the newly defined 165 kb Wolf-Hirschhorn syndrome critical region
Introduction
Results
   Patient analysis
   Expressed sequence identification
   cDNA mapping and characterisation
   GRAIL analysis
Discussion
Materials And Methods
   Cell lines
   DNA probes
   Fluorescent in situ hybridisation (FISH)
   Sequence analysis of the WHSCR
   GRAIL analysis of the WHSCR
   cDNA analysis
Acknowledgements
References

A transcript map of the newly defined 165 kb Wolf-Hirschhorn syndrome critical region

A transcript map of the newly defined 165 kb Wolf-Hirschhorn syndrome critical region Tracy J. Wright1, Darrell O. Ricke1, Karen Denison1, Simone Abmayr1, Philip D. Cotter2, Kurt Hirschhorn2,3, Mauri Keinänen4, Donna McDonald-McGinn5, Mirja Somer6, Nancy Spinner5, Theresa Yang-Feng7, Elaine Zackai5 and Michael R. Altherr1,8,*

1Genomics Group, Life Sciences Division, MS M888, Los Alamos National Laboratory, Los Alamos, NM 87545, USA, 2Department of Human Genetics and 3Department of Pediatrics, Mount Sinai School of Medicine, New York, NY 10029-6574, USA, 4Medix Clinical Laboratory, Nihtisillankuja 1, FIN-02630, Espoo, Finland, 5Department of Genetics, Wood Building, Children's Hospital, Philadelphia, PA 19104-4301, USA, 6Department of Medical Genetics, The Family Federation of Finland, PO Box 849, FIN-00101, Helsinki, Finland, 7Department of Genetics, Yale University, Box 3333, New Haven, CT 06510, USA and 8Department of Biological Chemistry, University of California at Irvine, Irvine, CA 92717, USA

Received September 12, 1996; Revised and Accepted November 20, 1996

Wolf-Hirschhorn syndrome (WHS) is a multiple malformation syndrome characterised by mental and developmental defects resulting from the absence of a segment of one chromosome 4 short arm (4p16.3). Due to the complex and variable expression of this disorder, it is thought that the WHS is a contiguous gene syndrome with an undefined number of genes contributing to the phenotype. In an effort to identify genes that contribute to human development and whose absence results in this syndrome, we have utilised a series of landmark cosmids to characterise a collection of WHS patient derived cell lines. Fluorescence in situ hybridisation with these cosmids was used to refine the WHS critical region (WHSCR) to 260 kb. The genomic sequence of this region is available and analysis of this sequence through BLAST detected several cDNA clones in the dbEST data base. A total of nine independent cDNAs, and their predicted translation products, from this analysis show no significant similarity to members of DNA or protein databases. Furthermore, these genes have been localised within the WHS critical region and reveal an interesting pattern of transcriptional organisation. A previously published report of apatient with proximal 4p- syndrome further refines the WHSCR to 165 kb defined by the loci D4S166 and D4S3327. This work provides the starting point to understand how multiple genes or other mechanisms can contribute to the complex phenotype associated with the Wolf-Hirschhorn syndrome.

INTRODUCTION

The Wolf-Hirschhorn syndrome (WHS) is a multiple malformation syndrome characterised by mental and developmental defects resulting from the partial deletion of the short arm of one chromosome 4 (4p16.3). WHS patients exhibit a constellation of symptoms including severe growth deficiency, severe to profound mental retardation with onset of convulsions by the second year of life, microcephaly, sacral dimples and characteristic facial features which include prominent glabella, hypertelorism, (`Greek helmet appearance') micrognathia, highly arched eyebrows, down-turned `carp' mouth and simple, lobeless ears. Other anomalies may include a variety of midline closure defects (cleft lip or palate, hypospadias, cryptorchidism), flexion/contracture deformities of hands and feet, skeletal defects (scoliosis, kyphosis), heart defects, hemangiomas, hypoplastic nipples and eye defects (microphthalmia, iris defects, cataracts, strabismus (1 -3 ).

The WHS phenotype was originally associated with cytogenetically observable alterations in the karyotype resulting from the terminal deletion of one 4p (4 -5 ). Subsequently, molecular techniques have been utilised to confirm the diagnosis of WHS where standard karyotype analysis failed to show a cryptic translocation (6 ) and small terminal or interstitial deletions (7 -8 ). These molecular analyses have been facilitated by the extensive physical maps and cloned resources available for 4p16.3 (9 -11 ). These resources have provided the basis on which to build the molecular foundation for this syndrome.

Previous studies excluded D4S43 and D4S168 from the critical region (12 -13 ). Due to the abundant cloned resources from this region of the genome, a large number of potential coding sequences have been identified (14 -17 ). In addition, one characterised gene, FGFR3, has been localised into this region. Overall, the region appears to be gene dense. Consequently, several potential coding sequences are present in this genomic segment that might contribute to the WHS phenotype.

As the critical region for this syndrome decreases, the number of patients that contribute to refining the region is significantly reduced. To expedite this process we had previously chosen a series of `landmark' cosmids for the analysis of patient cell lines by fluorescence in situ hybridisation (FISH) that extend across the terminal 4.5 Mb segment of 4p (13 ). Using this approach we have characterised one new patient and have further characterised three other patients. These analyses refine both the proximal and the distal boundaries of the WHS critical region (WHSCR).

The newly defined WHSCR is found in a region which has been sequenced. This genomic sequence was utilised to identify potential coding sequences and to build a transcription map of this contiguous gene syndrome.

RESULTS

Patient analysis

To expedite the localisation of deletion breakpoints in WHS patients, a series of landmark cosmids were employed to scan the genomic region from MSX1 to the subtelomeric locus D4F26 (13 ; Fig. 1 a). Cosmids were chosen which spanned this area with an average distance of 560 kb between loci. Following this preliminary analysis a second round of FISH was carried out using a series of overlapping cosmids which mapped between the landmarks (11 ; Fig. 1 b). This allowed localisation of the breakpoints to a specific cosmid within the region.


Figure 1. (A) Physical map of 4p16. The loci utilised in this and previous studies are shown above the line and the probes used in this study are shown below the line. The distance from D4S81 to the telomere is ~4.5 Mb. The genetic distance between MSX1 and D4S10 is 3 cM (44). The previously published critical region is depicted by solid boxes flanking the critical region defined by the WHS patients described in this study and depicted by an open box. The cross-hatched portion of the open box is the area that can be excluded when considering the 4p- syndrome patient (20). (B) Second tier cosmids used in FISH analysis determine the breakpoints in the patients defining the critical region. Cosmids are denoted by plate and row by column coordinates in the Los Alamos chromosome 4 library array. The continuous horizontal lines indicate the extent of the deletion in the designated patient, arrowheads indicate that the deletion continues either telomeric (CM) or centromeric (LGL7447).

In cell line CM fluorescence signals corresponding to the cosmid were detected on both chromosome 4 homologues using cosmids proximal to, and including, 10d12 (Fig. 1 a and b). Fluorescence signals corresponding to the cosmids including, and distal to, 193f8 were found on one chromosome 4. Therefore, CM contains a terminal deletion whose breakpoint lies within 108f12 (Fig. 1 b; defined by B4P19). This result defines the centromeric proximal boundary of WHS and correlates with previously published data which places the breakpoint less than 80 kb distal to D4S43 (12 ). The extent of the terminal deletion in this patient is ~2.5 Mb. In cell line HHW1839 fluorescence signals corresponding to the cosmid were detected on both chromosome 4 homologues using cosmids proximal to, and including, 139h8. Fluorescence signals corresponding to the cosmids including, and distal to, 65c1 were found on one chromosome 4. Therefore, HHW1839 contains a terminal deletion whose breakpoint lies between cosmids 139h8 and 65c1 (cosmids both located between D4S183 and D4S181; 11 ). The extent of the deletion in this patient is ~3 Mb. FISH analysis of the cell line MS2505 showed that cosmids distal to and including 33C6 (D4S43) were present on only one of the homologues. Fluorescence signals corresponding to the cosmids including, and proximal to, 247f6 were found on both chromosome 4 homologues. Therefore, MS2505 contains a terminal deletion with breakpoints between D4S182 and D4S43.

The distal breakpoint of the WHSCR was defined using the WHS derived cell line LGL7447. Fluorescence signals corresponding to the cosmid were detected on both chromosome 4 homologues using cosmids including, and distal to, 190b4 (Fig. 1 a and b). Fluorescence signals corresponding to the cosmid were detected on one chromosome 4 using cosmids including, and proximal to, 19h1. This places the distal breakpoint in this patient near the end of cosmids 190b4 and 19h1 (Fig. 1 b; defined by B4P20). The proximal breakpoint in LGL7447 is centromeric to MSX1. Therefore the extent of the interstitial deletion in this patient is likely to be at least 4.5 Mb. Comparing the smallest region of overlap in these patients reduces the WHSCR from 750 kb to ~260 kb which lies between the loci D4S132 (defined by cosmids 10d12 and 108f12) and D4S3327 (defined by cosmid 190b4).

Expressed sequence identification

The newly defined 260 kb WHSCR falls entirely within a 2 Mb cosmid contig (11 ) which has been sequenced by the Sanger Centre, UK. Sequences from the cosmids within the WHSCR and flanking region were aligned to form a contiguous sequence of the region. In light of continuing discussions of sequence data quality requirements by the Genome community, it is worth noting that we identified two inconsistencies in this data set. First, there are documented gaps in the sequence of the contig that render it less than complete. Second and probably most importantly for our analyses, five indel (base insertion or deletion ambiguity) errors were identified in a 7 kb overlap linking two clones (accession nos Z67997 and Z68226). Regardless of these minor problems, this sequence provides a wealth of information for analysis. The genomic sequence of this WHSCR was analysed through BLAST, Fasta and GRAIL using the programme Sequence Comparison ANalysis (SCAN; 18 ). A total of 42 cDNA clones were identified in dbEST. Alignment of both the 5' and 3' sequence in combination with the analysis of the position of the 3' sequence and the direction of transcription identified a total of nine independent sequences. One cDNA clone representing each set of sequence was chosen for further analysis. These cDNAs, and their predicted translation products, show no significant similarity to members of other DNA or protein databases. These clones were localised back to a specific cosmid using two different methods. Individual cDNAs were hybridised to EcoRI digests of cosmids within the critical region. In addition, the sequence from dbEST was analysed against the genomic sequence of the region using BLAST. Clones from TIGR (The Institute for Genomic Research) were sequenced with one primer and this sequence was localised to the genomic sequence (Table 1 ). Clones from the IMAGE consortium have been sequenced from both the 5' and 3' direction (Table 1 ). Thus a definitive position for the 3' and 5' ends of the IMAGE clones was derived (Table 1 ). This enabled the transcriptional orientation of these cDNA clones to be determined (Fig. 2 ). The results from the two techniques were compared to ensure that there were no discrepancies. Localisation of these cDNAs back to the cosmids provides a transcript map for the WHSCR (Fig. 2 ).


Figure 2. Transcription map of the WHSCR. A cosmid contig of the WHSCR and region immediately flanking is shown. The horizontal line indicates the position of the WHSCR. The position and direction of transcription, where known, of cDNAs is shown below the WHSCR. The broken line represents the region that can be excluded when considering the 4p- syndrome patient (20).

cDNA mapping and characterisation

The cDNA clones 53283, 267784 and 194164 mapped to cosmid 96a2; cDNA clones HHCJ43 and 153048 mapped to cosmid 174g8; cDNA clone 174766 mapped to cosmid 19h1; cDNA clone 44997 mapped to cosmid 19h1; sequence from cDNA clone 27812 mapped to cosmids 27h9 and 19h1. The cDNA clone HFBEP10 spanned cosmids 19h1 and 190b4 (Table 1 ; data not shown). Sequence analysis of HFBEP10 localised one end within cosmid 190b4. However, hybridisation with the cDNA clone to the cosmids detected signal in both cosmids 190b4 and 19h1. Therefore, the clone spans these cosmids and possibly spans the distal breakpoint of the WHSCR. All the cDNA clones map in the 165 kb WHSCR (Fig. 2 ).

The cDNA clones 27812, 53283 and 267784 are transcribed in the centromeric to telomeric direction. The cDNA clones 194164, 153048, 44997 and 174766 are transcribed in the opposite direction (Fig. 2 ). The direction of transcription of cDNA clones HFBEP10 and HHCJ43 could not be determined as sequence information has only been generated from one end. In addition to the orientation of the cDNA clones, alignment of the cDNA sequence to genomic sequence revealed intron-exon structures in cDNA clones 53283 and 267784. Sequence information from the cDNA clone 53283 showed that it contains at least four exons which are found over a 26.2 kb genomic region. The positions of these exons within cosmid 96a2 are bp 3048-3250, bp 20 270-20 442, bp 22 117-22 213 and bp 28 860-29 277 (Table 1 ). Three of the four exons were detected in the 5' sequence; these are 202, 173 and >96 bp. The 3' exon is >417 bp. Sequence information from the cDNA clone 267784 showed that it contains at least three exons which extend over a 10.6 kb genomic region. The positions of these exons within cosmid 96a2 are bp 18 616-19 112, bp 19 470-19 722 and bp 29 101-29 277 (Table 1 ). Two of the three exons are detected in the 3' sequence; these are 176 and >252 bp and the 5' exon is >496 bp. The cDNA clone 174766 has been sequenced completely (Table 1 ). The cDNA clone 174766 is ~600 bp and shows no intron-exon structure.

GRAIL analysis

GRAIL analysis of this region predicted a total of 109 exons. Thirty four GRAIL 2 exons were predicted in the WHSCR proximal genomic region (112 340 bp) and 75 GRAIL 2 exons in the cosmids spanning the WHSCR distal genomic region (180 430 bp). As eukaryotic gene organisation typically includes multiple exons, we have observed GRAIL gene predictions to be most reliable when clusters of exons are observed along a segment of genomic DNA sequence. Six clusters of GRAIL predicted exons were observed in the distal WHSCR genomic region (Fig. 3 b). However, only one cluster was observed in the proximal genomic region (Fig. 3 a). Of all of the GRAIL exon predictions, only three partially overlap with regions of EST homologies, all within the B2(F) GRAIL cluster (Fig. 3 b). Based on the GRAIL exon predictions, the distal region of the WHSCR has at least a three-fold higher density of human genes than the adjacent proximal genomic region.

DISCUSSION

In this study, we have utilised a series of previously defined landmark cosmids (13 ) to further analyse four WHS patients. The results of this analysis has refined the WHSCR from 750 kb (13 ) to a 260 kb region between the loci D4S132 (defined by the cosmid 108f12, Fig. 2 b) and D4S3327 (defined by the cosmid 190b4, Fig. 2 b). This implies that the set of genes responsible for the symptoms of WHS reside in this highly reduced region. This important advance renders manageable the identification and analysis of genes that contribute to this syndrome.

This further reduction of the WHSCR (from 750 to 260 kb) has excluded the only characterised gene, FGFR3, from the region. It is therefore crucial to isolate coding sequences from this region and to elucidate their role in both normal human development and in this contiguous gene syndrome. The 260 kb region maps entirely within a 2 Mb cosmid contig whose sequence is known (unpublished data, Sanger Centre, UK). Even though some minor incongruities remain unresolved, this data set provides an enormous wealth of information. The analysis of the sequence by BLAST detected 42 matches to cDNA clones in dbEST that appear to coalesce into nine distinct cDNAs. These, and their predicted translation products, show no significant similarity to members of DNA or protein databases, other than dbEST. Therefore, aside from the frequency of these sequences in tissue specific clone libraries, there is no indication for the biological function of these clones. Each of these cDNA clones has been localised to a specific cosmid within the WHSCR and the position of the 3' and 5' sequences within these cosmids has been defined. This transcript map provides the starting point for further characterisation and elucidation of the roles of these clones in both Wolf-Hirschhorn syndrome and normal human development.

Table 1 Analysis of cDNAs from the WHSCR 3' bp 29277-28860
cDNA clone

 GenBank

Cosmid

Sequence

Occurrence in
designation

 accession

 localisation

 localisation

 tissue specific
 

 number

  

  

 cDNA libraries
153048

 R50022

 174g8B

 5' bp 756-496

 breast (1)
 

 R50359

  

 3' bp 80-453

  
HHCJ43

 M62262

 174g8A

 bp 19426-19709

 hippocampus (1)
27812

 R13046

 27h9

 5' bp 27190-27493

 brain (3); placenta (3)
 

 R40477

 96a2

 3' bp 1149-882

  
53283

 R16217

 96a2

 5' bp 3048-3250;

brain (3); melanocyte (1)
 

 R16216

  

 20270-20443; 22117-22213

  
267784

 N32670

 96a2

 5' bp 18616-19112

 melanocyte (1)
 

 N23294

  

 3' bp 19470-19722;

  
 

  

  

 bp 29277-29101

  
194164

 H50987

 96a2

 5' bp 31002-30606

fetal liver/spleen (6)
 

 H51641

  

 3' bp 29825-30121

  
174766

 H30421

 19h1

 5' bp 33842-33439

brain (4)
 

 H39659

  

 3' bp 33258-33706

 fetal liver/spleen (4); placenta (2);

 

  

  

 multiple sclerosis (1)
44997

 H05214

 19h1

 5' bp 29494-28976

 aorta (6); brain (4);
 

 H05215

  

 3' bp 27977-28297

 fetal liver/spleen (1)
HFBEP10

 T07860

 190b4

 bp 18476-18200

 fetal brain (1)
The Genbank accession numbers associated with sequence from each cDNA clone have been given. The sequence localisation gives the coordinate position of this sequence within the cosmid. These cosmid coordinates are generated by the Sanger Centre, UK.


Figure 3. Computer predicted genes within the Wolf-Hirschhorn syndrome critical region. (A) GRAIL 2 exon predictions for the cosmids 108f12 to 206d7. The cluster of GRAIL exons is labeled A1 and (R) for the reverse strand. (B) GRAIL 2 exon predictions for the cosmids 174g8 to 190b4. Exon predictions and labeled EST homologies identify candidate genes with the WHSCR. Clusters of GRAIL exons on each strand are labeled B1-B6 with (F) for the forward strand and (R) for the reverse strand. Regions of EST identity are labeled with filled triangles (t for forward and s for reverse) or a filled diamond (strand orientation unknown) and a representative EST clone name.

Sequence analysis of these clones has shown that cDNA clone 53283 spans a 26.2 kb genomic region in cosmid 96a2 (as indicated in Table 1 ). Using the sequence found in dbEST for this clone it is possible to identify a 17 kb intron found within the 5' sequence. The 5' exon is 202 bp and the remainder of the 5' sequence falls into two exons (Table 1 ). The cDNA clone 267784 shares 175 bp of 3' sequence with cDNA clone 53283. The remainder of these sequences diverge from each other at bp 29 101 in cosmid 96a2. The 3' sequence in cDNA clone 53283 is contiguous with the genomic sequence and the remainder of the 3' sequence in cDNA clone 267784 is found 10 kb proximal at bp 19 725 in cosmid 96a2. The 5' sequence of cDNA clone 267784 begins at bp 18 696 in cosmid 96a2. This maps within the 17 kb intron of cDNA clone 53283. Therefore, it is highly likely that both these clones represent distinct genes.

GRAIL predictions of candidate exons complement the candidate exons identified by sequence similarity searching. Only three of the 19 regions of EST homologies partially overlap with GRAIL 2 exon predictions. The cDNAs represented by the ESTs were sequenced from one or both ends. The internal regions of the majority of these ESTs remain to be sequenced. For the B2(F) cluster of GRAIL exons (Fig. 3 b), additional overlaps between the GRAIL exons and the cDNAs are to be anticipated. The remaining clusters of GRAIL exons may well represent real genes which would not have been detected by EST or other database similarities. Conversely, eight cDNA clones are not closely associated with GRAIL exon predictions (Fig. 3 b). These observations support the value of both the GRAIL and sequence identity analyses. In addition, it is interesting to note that the cDNAs within the WHSCR reveal an uneven distribution. All the identified clones fall in the 165 kb WHSCR (Fig. 2 b).

The WHSCR can be further reduced by considering the analysis of a patient diagnosed with proximal 4p- syndrome (19 -20 ). This clinically distinct abnormality is caused by an interstitial deletion of the proximal short arm of chromosome 4. Cytogenetic analysis of this patient revealed an interstitial deletion involving band 4p14-4p16.1 (20 ). Molecular characterisation of a cell line derived from this patient determined the distal breakpoint to lie within D4S166 (21 ). As this patient does not have the `typical' anomalies associated with WHS (20 ) it is possible to exclude the region from D4S132 to D4S166 from the WHSCR. Consequently, while the critical region based on WHS patients alone is 260 kb, including this 4p- syndrome patient reduces the critical region to 165 kb. It is interesting to note that there were no cDNA clones identified in this region bounded by D4S132 and D4S166 (Fig. 2 ). In addition, only one of the clusters of potential GRAIL exons maps into the region (Fig. 3 a).

At present, three distinct clinically defined conditions have been associated with the loss of part of the short arm of chromosome 4. While the 4p- syndrome (20 -22 ) appears distinct from WHS, the Pitt-Rogers-Danks syndrome (PRD) displays a number of features similar to WHS but is generally less severe (23 ). PRD has recently been demonstrated to be associated with loss of material from distal 4p (24 ). Interestingly, there appears to be significant overlap in the genomic segments missing in these disorders making it likely that a number of the same genes contribute to these phenotypes. Efforts to identify the genes associated with a contiguous gene syndrome rely heavily on our ability to define the minimum critical region in which to search. These efforts are often hampered by variable expression of the phenotype. In this paper we report the molecular characterisation of one patient with a relatively small terminal deletion who has the hallmark features of WHS. In addition, we have extended the molecular analysis of three patients previously determined to have WHS. All of these patients have a partially deleted chromosome 4, display characteristically dysmorphic facies and some level of developmental delay. These patients have a small genomic region of overlap with the 4p- syndrome previously described.

A recent effort to generate a phenotypic map of 4p16 based on the characterisation of patients with 4p deletions (25 ) will certainly aid our search for the function of the genes identified in this study. While the characterisation of our patients is not completely concordant with the observations of Estabrooks (for example, the patient represented by cell line MS2505 has hypospadias but is not deleted for the segment from D4S10 to D4S127), it is tempting to associate cDNA clones with the phenotypic components of this disorder. In this regard, an intriguing candidate for the WHS associated congenital heart defect is represented by the cDNA clone 44997. This clone identified six independent clones in the dbEST database, that may represent a single message, generated from an aortic specific cDNA library. Similar phenotypic associations could be made for a number of the other cDNAs but a more worthwhile endeavor will be to look for the histological distributions of RNA corresponding to these cDNAs in the human and mouse tissues as a start to understanding their biological function.

How the genes identified in this study contribute to the WHS phenotype and its variability remains to be determined. The phenotype and pleiotropy associated with this syndrome may result from gene dose reduction, by the unmasking of deleterious alleles, by allelic variation in the remaining gene copy or a combination of these mechanisms. Furthermore, a single gene may be involved that serves as a `master' regulator and affects the expression of a number of other genes both at 4p and/or at other genomic locations. It is also possible that the deletion of a specific genomic segment or change in the position of the telomere alters the local chromosome structure in a way that affects gene expression in the vicinity of the chromosomal aberration. Studies to address these issues are underway.

In summary, this paper presents data that indicates that the WHSCR is contained within a 165 kb genomic segment. A total of nine independent cDNA clones were identified from the 42 matches generated during the sequence analysis of the WHSCR. In addition, several other potential coding sequences were predicted by GRAIL analysis of the genomic sequences. These coding sequences are all candidates for the abnormalities associated with WHS because they fall within the WHSCR and are deleted in all patients with this syndrome so far studied. This transcript map provides the starting point for analysis of the biological functions that contribute to the WHS phenotype.

MATERIALS AND METHODS

Cell lines

Cell line CM was derived from a WHS patient previously described in detail (12 ). She was noted to have microcephaly, a broad forehead with a prominent glabella, broad nose with a prominent nasal bridge and a short philtrum. Development was delayed and she developed a seizure disorder at 1 year. Previous analysis demonstrated that she had a terminal deletion of 4p16.3 with the breakpoint lying between D4S43 and D4S166.

Cell line HHW1839 was derived from a previously described WHS patient (26 ). He was described as having `Greek helmet appearance' with hypertelorism, down slanting to palpebral fissures, micrognathia and a high arched palate. Development was delayed and he was admitted for seizure control at 18 months.

Cell line LGL7447 was derived from a previously described WHS patient (27 ). She was described as having triangular facies, broad and prominent forehead, hypertelorism, antimongoloid slanting of the eyes, high nasal bridge with a broad nose and short philtrum. She had growth retardation and moderate developmental delay. Prometaphase studies showed a deletion between 4p15.32 and 4p16.3. FISH analysis showed that the loci D4F26 and D4S96 were intact in this patient.

Cell line MS2505 was derived from a 3 year old male with WHS. He had short stature, microcephaly, mild `Greek helmet appearance', seizures beginning at age 1 year, hypospadias and global delay.

DNA probes

A series of previously chosen landmark cosmids from 4p16.3 were utilised for FISH (13 ). Cosmids L228a7 (D4S81), L21f12 (D4S180), L247f6 (D4S182) and 33c6 (D4S43) spanning the published contig were obtained from the original flow sorted chromosome 4 arrayed library (11 ,28 ). Additionally, five other cosmids were obtained that provide landmarks for the remainder of 4pter: pC385.12 (containing the FGFR3 gene; 13 ), pC678 (D4S96; 2 ), CD2 (D4S90; 21 ), and pC847.351 (D4F26; 29 ). A cosmid containing the MSX1 gene, pWEHx712, was the most proximal marker used (30 ). Following FISH analysis with landmark cosmids, an additional round of analysis was carried out using a series of overlapping clones mapping between the landmark cosmids (11 ).

When STSs for a specific locus were available, the cosmid DNAs were verified by PCR amplification (31 ).

Fluorescent in situ hybridisation (FISH)

FISH was performed essentially as described (32 ). Biotinylated clone DNA (0.2 µg) was mixed with human Cot-1 fraction DNA to suppress repetitive sequences or block non-specific hybridisation. Hybridisation was detected using successive rounds of fluorescein (FITC) avidin D and biotinylated goat anti-avidin D (Vector Laboratories, Burlingame, CA).

Sequence analysis of the WHSCR

Cosmids from the 2 Mb contig of 4p16.3 (11 ) have been sequenced by the Sanger Centre, UK. The WHSCR now falls completely within this sequenced region. The cosmid sequences were compared against the GenBank (33 ), GenPept, PIR (34 ), SWISS-PROT (35 ), dbEST (database for `Expressed Sequence Tags') (36 ) and REPEAT databases with BLAST (37 -38 ) and Fasta (39 ) on local sequence analysis servers. These search results were integrated together with LANL's Sequence Comparison ANalysis (SCAN) programme (18 ). The SCAN programme reduced the results of the BLAST analysis to a summary report. Sequence similarity to repetitive sequences were listed by the best identity to the query sequence. To improve the detection of coding and repetitive sequences, SCAN parsed available annotation for GenBank and SWISS-PROT sequences. The SCAN results were reviewed from the text summary report and the WWW HTML summary report.

GRAIL analysis of the WHSCR

The WHSCR was analysed with XGRAIL (40 ) version 1.3c to identify potential exons. The sequences were aligned using the GCG LineUp program (41 ). The two sequence gaps within cosmid 174g8 were represented by the predicted gap sizes in the alignment. These gaps were converted to poly(C) regions by XGRAIL to eliminate exon predictions within the gaps.

cDNA analysis

cDNAs identified using SCAN were obtained from either IMAGE (42 ) or TIGR (43 ). Clones were grown under selective conditions and DNA was extracted using the Qiagen midi prep kit. cDNA clones were sized by double digestion of the clone to isolate the insert. Clones were localised by labeling linearised cDNAs using ECL (Amersham) and hybridisation to EcoRI digests of those cosmids from the WHSCR.

cDNAs from IMAGE have been sequenced from both the 3' and 5' ends of the clone. cDNAs from TIGR have been sequenced from one end. Sequence from these clones was localised within the WHSCR using BLAST (37 -38 ).

ACKNOWLEDGEMENTS

Funding for this project was provided by the US Department of Energy under contract # W-7405-ENG-36 (DR, MRA), the Los Alamos National Laboratory Directed Research and Development Fund (TW, KD, SA, MRA) and a grant from The Lehman Brothers Foundation (KH). We thank Dr Norman Doggett for his valuable comments during the preparation of the manuscript. We wish to acknowledge Dr John J. Wasmuth for his support, critical comments and enthusiasm in the formative stages of this project. The authors are grateful to Irina Gershin, Lisa Gibson and Nancy Owens for outstanding technical assistance.

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*To whom correspondence should be addressed

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