Human Molecular Genetics, 2002, Vol. 11, No. 23 2979-2987
© 2002 Oxford University Press
Okihiro syndrome is caused by SALL4 mutations
1Institut für Humangenetik, Universität Göttingen, Heinrich-Düker-Weg 12, 37073 Göttingen, Germany, 2Institut für Molekularbiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany, 3Clinical Genetics, Royal Devon and Exeter Hospital, Barrack Rd, Exeter, 4Dept Clinical and Molecular Genetics, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK and 5National Centre for Medical Genetics, Our Lady's Hospital for Sick Children, Crumlin, Dublin 12, Ireland
Received July 26, 2002; Accepted September 11, 2002
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
Okihiro syndrome refers to the association of forearm malformations with Duane syndrome of eye retraction. Based on the reported literature experience, clinical diagnosis of the syndrome can be elusive, owing to the variable presentation in families reported. Specifically, there is overlap of clinical features with other conditions, most notably Holt–Oram syndrome, a condition resulting from mutation of the TBX5 locus and Townes–Brocks syndrome, known to be caused by mutations in the SALL1 gene. Arising from our observation of several malformations in Okihiro syndrome patients which are also described in Townes–Brocks syndrome, we postulated that Okihiro syndrome might result from mutation of another member of the human SALL gene family. We have characterized the human SALL4 gene on chromosome 20q13.13–q13.2. Moreover, we have identified literature reports of forelimb malformations in patients with cytogenetically identifiable abnormalities of this region. We here present evidence in 5 of 8 affected families that mutation at this locus results in the Okihiro syndrome phenotype.
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
Duane anomaly, a congenital disorder of ocular motility, is a common condition and accounts for up to 1% of all cases of strabismus (1). It consists of limitation of eye abduction associated with retraction of the eye globe and narrowing of the palpebral fissure on adduction. Although it may occasionally be seen as a familial feature, usually transmitted in autosomal dominant fashion, most patients with Duane anomaly are sporadic cases. Loci for Duane anomaly have been mapped to chromosomes 2q (2), 4q (3), 8q (4,5) and 22 (6). However, gene mutations resulting in Duane anomaly have not been defined.
Careful examination of patients with Duane anomaly frequently uncovers associated anomalies, most commonly involving the external ear, hearing dysfunction, spinal and vertebral malformations, renal malformation and variable degrees of upper limb hypoplasia (7,8). Consequently, several clinical conditions have been delineated involving patients with Duane syndrome and associated malformations. However, it is unclear at present whether these conditions are truly distinct or whether several ‘overlap syndromes’ exist, representing variable expression of a single genetic entity. The London Dysmorphology Database lists 12 clinically distinct conditions with Duane anomaly (9). Okihiro syndrome is one such condition.
Okihiro syndrome refers to the familial occurrence of radial sided hand malformations in association with Duane anomaly and has been observed in several reports (10–15). The range of associated features among the families described is broad, encompassing anal stenosis, pigmentary disturbance, atrial septal defect, hearing impairment, renal abnormalities, external ear malformations and facial asymmetry in affected individuals. Significant intrafamilial variability is a feature of reported pedigrees.
SALL genes encode putative zinc finger transcription factors known to be important in human malformation syndromes, in that mutation at the SALL1 locus causes Townes–Brocks syndrome (16). Until recently, three genes had been identified within this gene family, but SALL2 and SALL3 have not yet been associated with disease phenotypes (17,18). SALL4 is a new member of this gene family, which has been localized to chromosome 20q13.13–q13.2 (19). We hypothesized that Okihiro syndrome might be the result of mutations of a human SALL gene. This hypothesis was based on the observation of occasional clinical features of Okihiro syndrome in patients with established mutations of human SALL1 as the cause of their malformations—specifically Duane anomaly, anal stenosis, deafness and external ear anomalies (20). The identification of SALL4 and the localization of that gene to human chromosome 20 strengthened our hypothesis, in that limb malformations have been reported in patients with chromosomal deletions which are likely to encompass the SALL4 region of chromosome 20 (21,22). Moreover, a phenotype with cardiac and limb anomalies, thought to represent a Holt–Oram presentation, has been reported with a de novo pericentric inversion of chromosome 20 involving a break point at q13.2 (23).
In this communication we report the characterization of the human SALL4 gene. To rest the hypothesis that mutation at this locus might cause Okihiro syndrome, we sought mutations in eight families. The study was specifically confined to families with Duane anomaly associated with radial limb malformation. We now present evidence that mutation at this locus causes Okihiro syndrome in 5 of the 8 families tested.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
SALL4 consists of 4 exons (3159 bp of coding sequence) and encodes three C2H2 double zinc finger domains of the SAL-type, the second of which has a single C2H2 zinc finger attached at its carboxy-terminal end, as well as an N-terminal C2HC zinc finger motif typical for vertebrate SAL-like proteins. Comparison of the amino acid sequences of SALL1, 2, and 3 with SALL4 suggests that SALL3 and 4 might have separated after duplication of a common ancestor gene (data not shown). While SALL3 encodes a fourth double zinc finger domain which seems to be spliced out preferentially from the mRNA (18), the corresponding coding sequence is replaced by intron 2 in SALL4. A schematic comparison of the human SALL proteins is shown in Figure 1.
|
Multiple tissue northern blot analysis with poly(A)+ RNA from various human adult organs revealed expression of a 5.5 kb transcript exclusively in adult testis but not in spleen, thymus, prostate, uterus, small intestine, colon, and peripheral blood lymphocytes (Fig. 2A). Expression was also not detected in adult pancreas, kidney, skeletal muscle, liver, lung, placenta, heart and brain tissue as determined by multiple tissue northern blot analysis (data not shown). RT–PCR confirmed expression in adult testis as well as lack of expression in brain, heart, lung, liver, kidney, and skeletal muscle but revealed faint SALL4 expression in ovary and spleen (Fig. 2C). Northern blot analysis with total RNA furthermore revealed SALL4 mRNA expression in embryonal carcinoma cell lines H12.1 and 2102 EP (24), respectively (Fig. 2B), but not in Jurkat, HeLa, and PC-3 cells (data not shown). In both SALL4 expressing cell lines but not in non-expressing tissues (data not shown), a second transcript of about 4 kb was observed (Fig. 2B). Since RT–PCR with primers positioned in exons 2 and 4 as well as in exons 1 and 2 suggested that there is no alternative splicing in SALL4 (data not shown), the second transcript might result from alternative polyadenylation. This hypothesis is strenghtened by the presence of two polyadenylation signals 198 bp and 1906 bp 3' of the stop codon in the SALL4 genomic sequence. Comparison of 4000 bp sequence 3' to the SALL4 stop codon with the human EST database revealed presence of highly homologous EST sequences only for the first 1906 bp, suggesting that the longest SALL4 transcript contains a 3'UTR of this size.
|
5.5 kb (arrow) only in testis tissue. (B) Northern blot containing human total RNA of embryonal carcinoma cell lines H12.1 (lane 1) and 2102 EP (lane 2) showing a prominent transcript of Eight unrelated families with Okihiro syndrome were analysed for SALL4 mutations (Fig. 3A–E) by amplification of the coding sequences of exons 1–4 and direct sequencing of SALL4 PCR products. In family 1 (14) the heterozygous nonsense mutation 1954C
T (Q652X) was detected which segregated with the clinical phenotype (Fig. 3A and B) in affected individuals (II.2, II.3, II.5, III.3, III.4, III.5) and was not observed in clinically unaffected individuals (I.2, II.1, II.4, II.6, III.1, III.2). Patient III.6 is clinically unaffected but does carry the mutation, being a non-manifesting heterozygote (Fig. 3A). Segregation of the mutation in the family was analysed by direct sequencing and confirmed by independent PCR and sequencing (data not shown).
|
In family 2 (unpublished), a heterozygous single base pair deletion 1053delG was found which leads to a frameshift and a preterminal stop codon 4 bp 3' of the deletion (Fig. 3B). This mutation, if not leading to nonsense-mediated decay of the mRNA of the mutant allele, would result in a putative prematurely terminated SALL4 protein lacking all double zinc fingers. Sequencing of PCR products showed that all affected family members carried the mutation. No samples were available from unaffected family members. Results were confirmed by independent PCR and sequencing (data not shown).
In patient III.1 of family 3 (Fig. 3C), direct sequencing analysis (data not shown) showed a heterozygous 842delG mutation also causing a frameshift and a premature stop codon 23 bp 3' to the deletion possibly resulting in a truncated SALL4 protein lacking all double zinc finger domains. The mutation creates a novel NlaIV restriction site and segregation of the mutation was analysed by restriction digest of a 639 bp (mutant) and 640 bp (wild-type) internal PCR fragment of exon 2. The mutation results in two novel fragments of 91 and 81 bp instead of the wild-type fragment of 173 bp. All affected but no unaffected family members from whom DNA was available showed the mutation (Fig. 3C). The limb malformations in this family were more severe than observed in the other families studied (Fig. 4C–F).
|
In family 4, direct sequencing showed a 2288C
A transition creating a preterminal stop codon (S763X) (Fig. 3D). The mutation was found in all three affected but not in the unaffected family members as determined by direct sequencing. Results were confirmed by independent PCR and sequencing (data not shown). In family 5, the 940–941insC insertion was detected only in the affected girl but not in her unaffected mother (Fig. 3E). The father was unavailable. This mutation causes a frameshift with a premature stop codon after 112 bp. Results were confirmed by independent PCR and sequencing (data not shown). All mutations reported were not found in 100 control chromosomes as determined by direct sequencing of PCR products. No SALL4 mutations were found in the remaining three families analysed.
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
Our results demonstrate that Okihiro syndrome is caused by truncating mutations of the gene SALL4 (Fig. 5). Based on the nature of the mutations we postulate that haploinsufficiency for SALL4 is underlying the malformations seen in Okihiro syndrome. Confirmation of haploinsufficiency as the underlying mechanism would require the observation of Okihiro syndrome in a patient with confirmed deletion of the SALL4 gene. However, in the absence of such a patient, a dominant or dominant-negative effect of the mutations or a residual activity of some mutant protein is still possible. Nonetheless, the available evidence favours haploinsufficiency for several reasons. Truncating mutations likely result in nonsense-mediated mRNA decay (25,26). Also, the limb malformations seen in patients with cytogenetic deletions of chromosome 20q, which probably encompass the SALL4 locus, would be consistent with this (21,22). Finally the nature of the sequence changes we report and the predicted effects of these are very similar to the spectrum of SALL1 mutations seen in Townes–Brocks syndrome (TBS), where only truncating mutations of SALL1 have been found in TBS patients (27). However, the mouse knock-out for the homologous Sall1 gene did not reveal a phenotype mimicking TBS (28). Instead, bilateral hypoplasia or aplasia of the kidneys were the only observed malformations suggesting that the pathogenic effect of truncating human SALL1 mutations could be different from haploinsufficiency. Alternatively, the different Sall genes could fulfill different functions between mouse and human.
|
The most severe limb phenotype observed, in Family 3, is caused by the most 5' positioned mutation (842delG), possibly leading to proteins without double zinc finger domains. A similar outcome in terms of protein structure would be expected of the 1053delG mutation. On the other hand, the limb phenotype of the 1053delG mutation is quite similar to the phenotype caused by mutations 1954C
T and 2288CA, resulting in proteins lacking only the third double zinc finger domain. Consequently, it is not possible to reach firm conclusions with respect to the limb phenotype in terms of mutation position, at this stage. Further families with SALL4 mutations and protein studies are needed to investigate any possible association between functional severity of mutation and the limb phenotype. In the forelimb, SALL4 mutation in the most severe cases leads to phocomelic limbs (Family 3; Fig. 3B, Fig. 4C–F). However the limb phenotype observed in most of our patients is milder, often involving the forearm, especially on the radial side, with associated thumb hypoplasia or reduplication. In a few instances, we have observed normal first metacarpal and carpal formation and the condition is manifest only by absence or hypoplasia of the thenar muscles (Fig. 4B). Additional clinical features seen in our patient cohort include anal stenosis (Families 4 and 5), external ear malformations (Families 2, 4 and 5), deafness (Families 2, 4 and 5), unilateral renal agenesis (Family 2), choanal stenosis (Family 2) and ventricular septal defect (Family 3). In addition to a key role in upper limb morphogenesis, these clinical features argue for SALL4 function during normal development in several other tissues, including the ear, cloacal membrane, heart and kidney. However, the relatively high frequency of unilateral renal agenesis and ventricular septal defects in the normal population must be borne in mind while interpreting this observation.
We present confirmation of SALL4 mutations as the basis of Okihiro syndrome. With one exception all patients reported have Duane retraction anomaly as a signal feature of the condition. The exception, case III.6 of Family 1, we interpret as a non-manifesting carrier of the condition. Study of published pedigrees establishes that non-manifesting obligate gene carriers are known in this disorder (8), thus supporting our view of the data in respect to this patient, in whose case the absence of Duane anomaly has been confirmed on formal examination. Moreover, the cosegregation of mutations with phenotype in the other families, the absence of mutations in control populations and the truncating nature of all mutations detected argue for a causal relationship between SALL4 mutations and Okihiro syndrome. There were no identifiable clinical differences between the five families in whom mutations were established and the three in whom we were unable to demonstrate mutation of SALL4, one of which has also been the subject of a previous report (13).
The London Dysmorphology Database (9) lists 12 clinically distinct conditions with Duane anomaly, Okihiro syndrome being one. However, dysmorphologists will recognize the overlap phenotypes among our patient cohort and it may prove instructive to seek SALL4 mutations in a wider patient population. Foremost among such syndromes might be Holt–Oram syndrome, a developmental anomaly characterized by radial forelimb anomalies, congenital heart malformations and associated features (29). Despite the identification of a causative locus for Holt–Oram syndrome at the TBX5 gene, only about 30% of clinically identified cases with this diagnosis have mutations of TBX5 (30). It is also noteworthy that a case of Holt–Oram syndrome has already been reported in association with a de novo pericentric inversion of chromosome 20, involving q13.2 (23). In light of the findings we present here, we would speculate that the subject of that report may have had Okihiro syndrome, arising from disruption of the SALL4 gene. Other clinical disorders which might be considered as candidates for mutation studies at SALL4 would be acro-reno-ocular syndrome (31), SALL1 mutation-negative Townes–Brocks syndrome as well as patients with isolated Duane anomaly. Additionally, the identification of malformations associated with SALL4 will facilitate the investigation of that group of patients with limb/cardiac anomalies originally considered to represent examples of Thalidomide embryopathy but in whose offspring the observation of similar anomalies has led to claims that Thalidomide is a mutagen as opposed to a teratogen (32).
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
Patients
Genomic DNA was collected from patients with Okihiro syndrome and unaffected relatives after obtaining their informed consent and with the approval of the Research Ethics Committee of Great Ormond Street Hospital for Children, London. The diagnosis of Okihiro syndrome was based on presence of Duane anomaly and upper limb malformations.
Northern blotting
For expression analysis of SALL4 a 32P-labelled probe of the IMAGE (33) clone 752642 (836 bp) was generated by use of rediprimeTM II labelling system (Amersham Biosciences, Freiburg, Germany) and hybridized to multiple tissue northern blots RPN4801 and RPN4803 containing polyA+ RNA of different adult human tissues (Amersham Biosciences) according to manufacturer's protocols and to northern blots with total RNA of human cell lines. RNA extraction, northern blotting and hybridization were carried out as described (34).
RT–PCR
2 µg of total RNA from adult human tissues (brain, heart, lung, liver, kidney, spleen, ovary, testis, skeletal muscle) were reverse transcribed using Ready-To-GoTM You-Prime First Strand Beads (Amersham Biosciences PeqLab, Erlangen, Germany) and 20 pmol each of primers SA4RTS2 and HPRTR (5'-GTCAAGGGCATATCCTACAACAAAC-3') according to the manufacturers instructions. 1 µl of each first strand reaction was used as a template in two subsequent PCR reactions with primers 1) SA4E2S6N and SA4RTR2 (amplifying a 929 bp SALL4 fragment), and 2) HPRTF (5'-CCTGCTGGATTACATCAAAGCACTG-3') and HPRTR. Primer sequences for HPRT were derived from the HPRT cDNA sequence (35). Fragments were amplified in 1x polymerase buffer with 1.5 mM MgCl2, 10 mM Tris pH 8.0, 50 mM KCl using 1 µl of template cDNA, 100 µM dNTPs, primers 0.5 µM each, and 1 U Platinum Taq polymerase (Invitrogen, Karlsruhe, Germany). Cycling conditions were: 95°C for 4 min followed by 35 cycles of amplification (1 min, 94°C; 1 min, 64°C; 1 min, 72°C) and a final elongation step at 72°C for 3 min on a Perkin Elmer/Cetus (Weiterstadt, Germany) thermocycler. Amplification products were visualized on agarose gels. The DNA sequence of the SALL4 amplification product was verified by direct sequencing.
Genetic analysis
Genomic DNA was prepared from peripheral lymphocytes by routine procedures. Primers for amplification and direct sequencing of exons 1–4 are shown in Table 1. A 1560 bp fragment encompassing exon 1 was amplified with primers SA4E1F3 and SA4E1R3. Exon 2 was amplified with primers SA4E2F6 and SA4E2R3 (5095 bp) followed by a nested amplification with primers SA4E2F5 and SA4E2R2 resulting in a fragment of 4051 bp (Table 1). Exon 3 was amplified with SA4E3F1 and SA4E3R1 primers (456 bp fragment), exon 4 (coding region; 660 bp fragment) with primers SA4E4F1 and SA4E4R1. Exons 1 and 2 were amplified using the SAWADY Mid Range PCR system (PeqLab) according to the manufacturer's instructions (annealing temperature 64°C; Perkin Elmer/Cetus thermocycler). Exons 3 and 4 were amplified in 1x polymerase buffer with 1.5 mM MgCl2, 10 mM Tris pH 8.0, 50 mM KCl using 100 ng of template genomic DNA, 100 µM dNTPs, primers 0.5 µM each, and 1 U Platinum Taq polymerase (Invitrogen). The cycling parameters were: 95°C for 4 min followed by 35 cycles of amplification (1 min, 94°C; 1 min, 64°C; 40 sec, 72°C) and a final elongation step at 72°C for 3 min on a Perkin Elmer/Cetus thermocycler. PCR products were analysed on 0.7% (exons 1 and 2) or 1% (exons 3 and 4) agarose gels, the fragments gel purified using the QIAquick gel extraction system (Qiagen, Hilden, Germany), cycle sequenced (primers see Table 1) using the ET Terminator Kit (Amersham Biosciences) and analysed on a MegaBace automated sequencer (Amersham Biosciences) following the manufacturer's protocol.
|
Mutations in family 1 (1954C
T) and family 4 (2288CA) were detected by direct sequencing of exon 2 with primers SA4E2S5N and SA4E2S6N (Table 1), respectively. Mutations in families 2 and 5 (1053delG, family 2; 940–941insC, family 5) were detected by direct sequencing of exon 2 with primers SA4E2S3N (Table 1). The mutation in family 3 (842delG) was confirmed and analysed for segregation by internal amplification of exon 2 (640 bp, wild-type; 639 bp, mutant) with primers SA4F581 and SA4R1281 (Table 1). PCR products were ethanol precipitated and restriction digested with NlaIV according to the manufacturers instructions (New England Biolabs, Beverly, MA, USA). Restriction fragments were separated on a 2.5% agarose gel and visualized by ethidium bromide staining.
GenBank accession numbers
SALL4 mRNA, NM_020436. Genomic contig NT_011362.
|
ACKNOWLEDGEMENTS |
|---|
We would like to thank the families for their participation, generosity and patience. We would also like to thank H.-U. Pauer and P. Burfeind for discussion and comments, W. Engel for review and support and M. Möschner and U. Teske for technical assistance. W.R. wishes to specifically acknowledge M. Bitner for phlebotomy in family 1. Family 4 was brought to our attention by Richard Trembath. W.R. is supported by The Children's Medical and Research Foundation at Our Lady's Hospital for Sick Children. This work was funded by the Wilhelm-Sander-Stiftung (grant 98.075.2 to J.K.).
|
FOOTNOTES |
|---|
* To whom correspondence should be addressed at: Institute for Human Genetics, University of Göttingen, Heinrich-Düker-Weg 12, 37073 Göttingen, Germany. Email: jkohlha{at}gwdg.de
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
1 Kirkham, T.H. (1970) Inheritance of Duane's syndrome. Br. J. Ophthalmol., 54, 323–329.
2 Appukuttan, B., Gillanders, E., Juo, S.H., Freas-Lutz, D., Ott, S., Sood, R., Van Auken, A., Bailey-Wilson, J., Wang, X., Patel, R.J. et al. (1999) Localization of a gene for Duane retraction syndrome to chromosome 2q31. Am. J. Hum. Genet., 65, 1639–1646.[ISI][Medline]
3 Chew, C.K., Foster, P., Hurst, J.A. and Salmon, J.F. (1995) Duane's retraction syndrome associated with chromosome 4q27–31 segment deletion. Am. J. Ophthalmol., 119, 807–809.[ISI][Medline]
4
Vincent, C., Kalatzis, V., Compain, S., Levilliers, J., Slim, R., Graia, F., Pereira, M.L., Nivelon, A., Croquette, M.F., Lacombe, D. et al. (1994) A proposed new contiguous gene syndrome on 8q consists of Branchio–Oto–Renal (BOR) syndrome, Duane syndrome, a dominant form of hydrocephalus and trapeze aplasia; implications for the mapping of the BOR gene. Hum. Mol. Genet., 3, 1859–1866.
5 Rickard, S., Parker, M., van't Hoff, W., Barnicoat, A., Russell-Eggitt, I., Winter, R.M. and Bitner-Glindzicz, M. (2001) Oto–facio–cervical (OFC) syndrome is a contiguous gene deletion syndrome involving EYA1 : molecular analysis confirms allelism with BOR syndrome and further narrows the Duane syndrome critical region to 1 cM. Hum. Genet., 108, 398–403.[ISI][Medline]
6 Cullen, P., Rodgers, C.S., Callen, D.F., Connolly, V.M., Eyre, H., Fells, P., Gordon, H., Winter, R.M. and Thakker, R.V. (1993) Association of familial Duane anomaly and urogenital abnormalities with a bisatellited marker derived from chromosome 22. Am. J. Med. Genet., 47, 925–930.[ISI][Medline]
7 Pfaffenbach, D.D., Cross, H.E. and Kearns, T.P. (1972) Congenital anomalies in Duane's retraction syndrome. Arch. Ophthalmol., 88, 635–639.[ISI][Medline]
8 Hayes, A., Costa, T. and Polomeno, R.C. (1985) The Okihiro syndrome of Duane anomaly, radial ray abnormalities, and deafness. Am. J. Med. Genet., 22, 273–280.[ISI][Medline]
9 Winter, R.M. and Baraitser, M. (2001) London Dysmorphology Database. Oxford University Press, Oxford.
10 Ferrell, R.L., Jones, B. and Lucas, R.V. Jr. (1966) Simultaneous occurrence of the Holt–Oram and the Duane syndromes. J. Pediatr., 69, 630–634.[ISI][Medline]
11 Okihiro, M.M., Tasaki, T., Nakano, K.K. and Bennett, B.K. (1977) Duane syndrome and congenital upper-limb anomalies. A familial occurrence. Arch. Neurol., 34, 174–179.[Abstract]
12 Temtamy, S.A. and McKusick, V.A. (1978) The genetics of hand malformations. Birth Defects Orig. Artic. Ser., 14, 1–619.[Medline]
13 MacDermot, K. and Winter, R. (1987) Radial ray defect and duane anomaly: report of a family with autosomal dominant transmission. Am. J. Med. Genet., 27, 313–319.[ISI][Medline]
14 Collins, A., Baraitser, M. and Pembrey, M. (1993) Okihiro syndrome: thenar hypoplasia and Duane anomaly in three generations. Clin. Dysmorphol., 2, 237–240.[Medline]
15 Chun, B.B., Mazzoli, R.A. and Raymond, W.R. (2001) Characteristics of Okihiro syndrome. J. Pediatr. Ophthalmol. Strabismus, 38, 235–239.[ISI][Medline]
16 Kohlhase, J., Wischermann, A., Reichenbach, H., Froster, U. and Engel, W. (1998) Mutations in the SALL1 putative transcription factor gene cause Townes–Brocks syndrome. Nat. Genet., 18, 81–83.[ISI][Medline]
17 Kohlhase, J., Schuh, R., Dowe, G., Kühnlein, R.P., Jäckle, H., Schroeder, B., Schulz-Schaeffer, W., Kretzschmar, H.A., Köhler, A., Müller, U. et al. (1996) Isolation, characterization, and organ-specific expression of two novel human zinc finger genes related to the Drosophila gene spalt. Genomics, 38, 291–298.[ISI][Medline]
18 Kohlhase, J., Hausmann, S., Stojmenovic, G., Dixkens, C., Bink, K., Schulz-Schaeffer, W., Altmann, M. and Engel, W. (1999) SALL3, a new member of the human spalt-like gene family, maps to 18q23. Genomics, 62, 216–222.[ISI][Medline]
19 Deloukas, P., Matthews, L.H., Ashurst, J., Burton, J., Gilbert, J.G., Jones, M., Stavrides, G., Almeida, J.P., Babbage, A.K., Bagguley, C.L. et al. (2001) The DNA sequence and comparative analysis of human chromosome 20. Nature, 414, 865–871.[Medline]
20 Kohlhase, J., Taschner, P., Burfeind, P., Pasche, B., Newman, B., Blanck, C., Breuning, M., ten Kate, L., Maaswinkel-Mooy, P., Mitulla, B. et al. (1999) Molecular analysis of SALL1 mutations in Townes–Brocks syndrome. Am. J. Hum. Genet., 64, 435–445.[ISI][Medline]
21 Fraisse, J., Bertheas, M.F., Frere, F., Lauras, B., Rolland, M.O. and Brizard, C.P. (1981) Un nouveau syndrome: del (20) (q13–qter). Localisation segmentaire de gene de l'adenosine deaminase (ADA). Ann. Genet., 24, 216–219.[ISI][Medline]
22 Shabtai, F., Ben-Sasson, E., Arieli, S. and Grinblat, J. (1993) Chromosome 20 long arm deletion in an elderly malformed man. J. Med. Genet., 30, 171–173.[Abstract]
23 Yang, S., Sherman, S., Derstine, J. and Schonberg, S. (1990) Holt–Oram gene may be on chromosome 20. Pediatr. Res., 27, 137A.
24 Casper, J., Schmoll, H.-J., Schnaidt, U. and Fonatsch, C. (1987) Cell lines of human germinal cancer. Int. J. Androl., 10, 105–113.[ISI][Medline]
25 Culbertson, M.R. (1999) RNA surveillance. Unforeseen consequences for gene expression, inherited genetic disorders and cancer. Trends Genet., 15, 74–80.[ISI][Medline]
26 Hentze, M.W. and Kulozik, A.E. (1999) A perfect message: RNA surveillance and nonsense-mediated decay. Cell, 96, 307–310.[ISI][Medline]
27 Kohlhase, J. (2000) SALL1 mutations in Townes–Brocks syndrome and related disorders. Hum. Mut., 16, 460–466.[ISI][Medline]
28 Nishinakamura, R., Matsumoto, Y., Nakao, K., Nakamura, K., Sato, A., Copeland, N., Gilbert, D., Jenkins, N., Scully, S., Lacey, D. et al. (2001) Murine homolog of SALL1 is essential for ureteric bud invasion in kidney development. Development, 128, 3105–3115.[Medline]
29 Newbury-Ecob, R.A., Leanage, R., Raeburn, J.A. and Young, I.D. (1996) Holt–Oram syndrome: a clinical genetic study. J. Med. Genet., 33, 300–307.[Abstract]
30
Cross, S.J., Ching, Y.H., Li, Q.Y., Armstrong–Buisseret, L., Spranger, S., Lyonnet, S., Bonnet, D., Penttinen, M., Jonveaux, P., Leheup, B. et al. (2000) The mutation spectrum in Holt–Oram syndrome. J. Med. Genet., 37, 785–787.
31
Becker, K., Beales, P.L., Calver, D.M., Matthijs, G. and Mohammed, S.N. (2002) Okihiro syndrome and acro-renal-ocular syndrome: clinical overlap, expansion of the phenotype, and absence of PAX2 mutations in two new families. J. Med. Genet., 39, 68–71.
32
McBride, W.G. (1994) Thalidomide may be a mutagen. Br. Med. J., 308, 1635–1636.
33 Lennon, G., Auffray, C., Polymeropoulos, M. and Soares, M.B. (1996) The I.M.A.G.E. Consortium: an integrated molecular analysis of genomes and their expression. Genomics, 33, 151–152.[ISI][Medline]
34 Buck, A., Archangelo, L., Dixkens, C. and Kohlhase, J. (2000) Molecular cloning, chromosomal localization, and expression of the murine SALL1 ortholog Sall1. Cytogenet. Cell Genet., 89, 150–153.[ISI][Medline]
35
Jolly, D.J., Okayama, H., Berg, P., Esty, A.C., Filpula, D., Bohlen, P., Johnson, G.G., Shively, J.E., Hunkapillar, T. and Friedmann, T. (1983) Isolation and characterization of a full-length expressible cDNA for human hypoxanthine phosphoribosyl transferase. Proc. Natl Acad. Sci. USA., 80, 477–481.
36 Kühnlein, R.P., Frommer, G., Friedrich, M., Gonzalez-Gaitan, M., Weber, A., Wagner-Bernholz, J.F., Gehring, W., Jäckle, H. and Schuh, R. (1994) spalt encodes an evolutionary conserved zinc finger protein of novel structure which provides homeotic gene function in the head and tail region of the Drosophila embryo. EMBO J., 13, 168–179.[ISI][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. Yang, L. Chai, C. Gao, T. C. Fowles, Z. Alipio, H. Dang, D. Xu, L. M. Fink, D. C. Ward, and Y. Ma SALL4 is a key regulator of survival and apoptosis in human leukemic cells Blood, August 1, 2008; 112(3): 805 - 813. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Harrison, R. Nishinakamura, and A. P. Monaghan Sall1 Regulates Mitral Cell Development and Olfactory Nerve Extension in the Developing Olfactory Bulb Cereb Cortex, July 1, 2008; 18(7): 1604 - 1617. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Demer, R. A. Clark, K. H. Lim, and E. C. Engle Magnetic Resonance Imaging of Innervational and Extraocular Muscle Abnormalities in Duane-Radial Ray Syndrome Invest. Ophthalmol. Vis. Sci., December 1, 2007; 48(12): 5505 - 5511. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Lauberth, A. C. Bilyeu, B. A. Firulli, K. L. Kroll, and M. Rauchman A Phosphomimetic Mutation in the Sall1 Repression Motif Disrupts Recruitment of the Nucleosome Remodeling and Deacetylase Complex and Repression of Gbx2 J. Biol. Chem., November 30, 2007; 282(48): 34858 - 34868. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Yang, L. Chai, F. Liu, L. M. Fink, P. Lin, L. E. Silberstein, H. M. Amin, D. C. Ward, and Y. Ma Bmi-1 is a target gene for SALL4 in hematopoietic and leukemic cells PNAS, June 19, 2007; 104(25): 10494 - 10499. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Pierpont, C. T. Basson, D. W. Benson Jr, B. D. Gelb, T. M. Giglia, E. Goldmuntz, G. McGee, C. A. Sable, D. Srivastava, and C. L. Webb Genetic Basis for Congenital Heart Defects: Current Knowledge: A Scientific Statement From the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: Endorsed by the American Academy of Pediatrics Circulation, June 12, 2007; 115(23): 3015 - 3038. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. C. Engle Genetic Basis of Congenital Strabismus Arch Ophthalmol, February 1, 2007; 125(2): 189 - 195. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Yamashita, A. Sato, M. Asashima, P.-C. Wang, and R. Nishinakamura Mouse homolog of SALL1, a causative gene for Townes-Brocks syndrome, binds to A/T-rich sequences in pericentric heterochromatin via its C-terminal zinc finger domains. Genes Cells, February 1, 2007; 12(2): 171 - 182. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. C. Engle, C. Andrews, K. Law, and J. L. Demer Two Pedigrees Segregating Duane's Retraction Syndrome as a Dominant Trait Map to the DURS2 Genetic Locus Invest. Ophthalmol. Vis. Sci., January 1, 2007; 48(1): 189 - 193. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Hasson, J. Del Buono, and M. P. O. Logan Tbx5 is dispensable for forelimb outgrowth Development, January 1, 2007; 134(1): 85 - 92. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Wu, X. Chen, J. Zhang, Y.-H. Loh, T.-Y. Low, W. Zhang, W. Zhang, S.-K. Sze, B. Lim, and H.-H. Ng Sall4 Interacts with Nanog and Co-occupies Nanog Genomic Sites in Embryonic Stem Cells J. Biol. Chem., August 25, 2006; 281(34): 24090 - 24094. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sakaki-Yumoto, C. Kobayashi, A. Sato, S. Fujimura, Y. Matsumoto, M. Takasato, T. Kodama, H. Aburatani, M. Asashima, N. Yoshida, et al. The murine homolog of SALL4, a causative gene in Okihiro syndrome, is essential for embryonic stem cell proliferation, and cooperates with Sall1 in anorectal, heart, brain and kidney development Development, August 1, 2006; 133(15): 3005 - 3013. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Harvey and M. P. O. Logan sall4 acts downstream of tbx5 and is required for pectoral fin outgrowth. Development, March 1, 2006; 133(6): 1165 - 1173. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Yamada, D. G. Hunter, C. Andrews, and E. C. Engle A Novel KIF21A Mutation in a Patient With Congenital Fibrosis of the Extraocular Muscles and Marcus Gunn Jaw-Winking Phenomenon Arch Ophthalmol, September 1, 2005; 123(9): 1254 - 1259. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T Tukel, A Uzumcu, A Gezer, H Kayserili, M Yuksel-Apak, O Uyguner, S H Gultekin, H-C Hennies, P Nurnberg, R J Desnick, et al. A new syndrome, congenital extraocular muscle fibrosis with ulnar hand anomalies, maps to chromosome 21qter J. Med. Genet., May 1, 2005; 42(5): 408 - 415. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W Borozdin, D Boehm, M Leipoldt, C Wilhelm, W Reardon, J Clayton-Smith, K Becker, H Muhlendyck, R Winter, O Giray, et al. SALL4 deletions are a common cause of Okihiro and acro-renal-ocular syndromes and confirm haploinsufficiency as the pathogenic mechanism J. Med. Genet., September 1, 2004; 41(9): e113 - e113. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Parrish, T. Ott, C. Lance-Jones, G. Schuetz, A. Schwaeger-Nickolenko, and A. P. Monaghan Loss of the Sall3 Gene Leads to Palate Deficiency, Abnormalities in Cranial Nerves, and Perinatal Lethality Mol. Cell. Biol., August 15, 2004; 24(16): 7102 - 7112. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W Borozdin, M J Wright, R C M Hennekam, M C Hannibal, Y J Crow, T E Neumann, and J Kohlhase Novel mutations in the gene SALL4 provide further evidence for acro-renal-ocular and Okihiro syndromes being allelic entities, and extend the phenotypic spectrum J. Med. Genet., August 1, 2004; 41(8): e102 - e102. [Full Text] [PDF]
|
|
|
|
|
|
D. Li, Y. Tian, Y. Ma, and T. Benjamin p150Sal2 Is a p53-Independent Regulator of p21WAF1/CIP Mol. Cell. Biol., May 1, 2004; 24(9): 3885 - 3893. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Kiefer, K. K. Ohlemiller, J. Yang, B. W. McDill, J. Kohlhase, and M. Rauchman Expression of a truncated Sall1 transcriptional repressor is responsible for Townes-Brocks syndrome birth defects Hum. Mol. Genet., September 1, 2003; 12(17): 2221 - 2227. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. T.F.M. Verzijl, B. van der Zwaag, J. R.M. Cruysberg, and G. W. Padberg Mobius syndrome redefined: A syndrome of rhombencephalic maldevelopment Neurology, August 12, 2003; 61(3): 327 - 333. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
|