Stress-related growth following sport injury: Examining the applicability of the organismic valuing theory.

This study explored the applicability of organismic valuing theory (OVT) to stress-related growth (SRG) following sport injury. Specifically, the direct and indirect relationships between need satisfaction (i.e., autonomy, competence, and relatedness), SRG, and subjective well-being (i.e., positive affect) were examined. Previously injured athletes (n = 520), ranging from 18 to 59 years of age (Mage = 23.3 years; standard deviation = 6.5), completed three measures: needs satisfaction scale, stress-related growth scale, and positive affect scale. Structural equation modeling with maximum likelihood estimation revealed a significant positive relationship between competence and relatedness and SRG, and between SRG and positive affect. In line with OVT, SRG was also found to mediate the relationship between need satisfaction (competence and relatedness) and subjective well-being. The findings offer preliminary support for the applicability of OVT in aiding our understanding of the antecedents and consequences of SRG. Future avenues of research are discussed, together with recommended methodologies to further extend and refine knowledge and understanding of the phenomenon of SRG following sport injury.

A homeobox gene, HLXB9, is the major locus for dominantly inherited sacral agenesis.

Partial absence of the sacrum is a rare congenital defect which also occurs as an autosomal dominant trait; association with anterior meningocoele, presacral teratoma and anorectal abnormalities constitutes the Currarino triad (MIM 176450). Malformation at the caudal end of the developing notochord at approximately Carnegie stage 7 (16 post-ovulatory days), which results in aberrant secondary neurulation, can explain the observed pattern of anomalies. We previously reported linkage to 7q36 markers in two dominantly inherited sacral agenesis families. We now present data refining the initial subchromosomal localization in several additional hereditary sacral agenesis (HSA) families. We excluded several candidate genes before identifying patient-specific mutations in a homeobox gene, HLXB9, which was previously reported to map to 1q41-q42.1 and to be expressed in lymphoid and pancreatic tissues.

Direct selection of conserved cDNAs from the DiGeorge critical region: isolation of a novel CDC45-like gene.

We have used a modified direct selection technique to detect transcripts that are both evolutionary conserved and developmentally expressed. The enrichment for homologous mouse cDNAs by use of human genomic DNA as template is shown to be an efficient and rapid approach for generating transcript maps. Deletions of human 22q11 are associated with several clinical syndromes, with overlapping phenotypes, for example, velocardiofacial syndrome (VCFS) and DiGeorge syndrome (DGS). A large number of transcriptional units exist within the defined critical region, many of which have been identified previously by direct selection. However, no single obvious candidate gene for the VCFS/DGS phenotype has yet been found. Our technique has been applied to the DiGeorge critical region and has resulted in the isolation of a novel candidate gene, Cdc45l2, similar to yeast Cdc45p. [The sequence data described in this paper have been submitted to the EMBL data library under accession nos. AJ0223728 and AF0223729.]

Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients.

Velo-cardio-facial syndrome (VCFS) is a relatively common developmental disorder characterized by craniofacial anomalies and conotruncal heart defects. Many VCFS patients have hemizygous deletions for a part of 22q11, suggesting that haploinsufficiency in this region is responsible for its etiology. Because most cases of VCFS are sporadic, portions of 22q11 may be prone to rearrangement. To understand the molecular basis for chromosomal deletions, we defined the extent of the deletion, by genotyping 151 VCFS patients and performing haplotype analysis on 105, using 15 consecutive polymorphic markers in 22q11. We found that 83% had a deletion and >90% of these had a similar approximately 3 Mb deletion, suggesting that sequences flanking the common breakpoints are susceptible to rearrangement. We found no correlation between the presence or size of the deletion and the phenotype. To further define the chromosomal breakpoints among the VCFS patients, we developed somatic hybrid cell lines from a set of VCFS patients. An 11-kb resolution physical map of a 1,080-kb region that includes deletion breakpoints was constructed, incorporating genes and expressed sequence tags (ESTs) isolated by the hybridization selection method. The ordered markers were used to examine the two separated copies of chromosome 22 in the somatic hybrid cell lines. In some cases, we were able to map the chromosome breakpoints within a single cosmid. A 480-kb critical region for VCFS has been delineated, including the genes for GSCL, CTP, CLTD, HIRA, and TMVCF, as well as a number of novel ordered ESTs.

Identification of a novel transcript disrupted by a balanced translocation associated with DiGeorge syndrome.

Most cases of DiGeorge syndrome (DGS) and related abnormalities are associated with deletions within 22q11. Shortest region of deletion overlap (SRO) mapping previously identified a critical region (the DGCR) of 500 kb, which was presumed to contain a gene or genes of major effect in the haploinsufficiency syndromes. The DGCR also contains sequences disrupted by a balanced translocation that is associated with DGS--the ADU breakpoint. We have cloned sequences at the breakpoint and screened for novel genes in its vicinity. A series of alternatively spliced transcripts expressed during human and murine embryogenesis, but with no obvious protein encoding potential, were identified. The gene encoding these RNAs has been named DGCR5 and it is disrupted by the patient ADU breakpoint. DGCR5 is distinct from the DGCR3 open reading frame (ORF) previously shown to be interrupted by the ADU translocation, although DGCR3 is embedded within a DGCR5 intron and in the same (predicted) transcriptional orientation. No mutations of DGCR5 have yet been detected. By analogy to other loci encoding conserved, nontranslated RNAs, it is possible that DGCR5 originates from a cis-acting transcriptional control element in the vicinity of the ADU/VDU breakpoint. Disruption of such an element would result in altered transcription of neighboring genes secondary to a position effect, a hypothesis in keeping with recent refinement of the SRO placing the ADU breakpoint outside the DGCR.

Isolation of a gene encoding an integral membrane protein from the vicinity of a balanced translocation breakpoint associated with DiGeorge syndrome.

Deletions within 22q11 have been associated with a wide variety of birth defects embraced by the acronym CATCH22 and including the DiGeorge syndrome, Shprintzen syndrome (velocardiofacial syndrome) and congenital heart disease. It is not known how many genes contribute to this phenotype. Previous studies have shown that a balanced translocation disrupts sequences within the shortest region of deletion overlap for DiGeorge syndrome. A P1 clone was isolated which spans this breakpoint and used to isolate a cDNA encoding a transmembrane protein expressed in a wide variety of tissues. This gene (called IDD) is not disrupted by the translocation, but maps within 10 kb of the breakpoint. Mutation analysis of five affected cases with no previously identified chromosome 22 deletion was negative, but a potential protein polymorphism was discovered. No deletions or rearrangements were detected in these patients following analysis with markers closely flanking the breakpoint, data which emphasize that large (i.e. over 1 Mb) interstitial deletions are the rule in DiGeorge syndrome. The proximity of IDD to the balanced translocation breakpoint and its position within the shortest region of deletion overlap indicate that this gene may have a role, along with other genes, in the CATCH22 haploinsufficiency syndromes.

Isolation of a putative transcriptional regulator from the region of 22q11 deleted in DiGeorge syndrome, Shprintzen syndrome and familial congenital heart disease.

A wide spectrum of birth defects are caused by deletions of the DiGeorge syndrome critical region (DGCR) at human chromosome 22q11. Over one hundred such deletions have now been examined and a minimally deleted region of 300kb defined. Within these sequences we have identified a gene expressed during human and murine embryogenesis. The gene, named TUPLE1, and its murine homologue, encodes a protein containing repeated motifs similar to the WD40 domains found in the beta-transducin/enhancer of split (TLE) family. The TUPLE1 product has several features typical of transcriptional control proteins and in particular has homology with the yeast Tup1 transcriptional regulator. We propose that haploinsufficiency for TUPLE1 is at least partly responsible for DiGeorge syndrome and related abnormalities.

Isolation of a new marker and conserved sequences close to the DiGeorge syndrome marker HP500 (D22S134).

End fragment cloning from a YAC at the D22S134 locus allowed the isolation of a new probe HD7k. This marker detects hemizygosity in two patients previously shown to be dizygous for D22S134. This positions the distal deletion breakpoint in these patients to the sequences within the YAC, and confirms that HD7k is proximal to D22S134. In a search for coding sequences within the region commonly deleted in DGS we have identified a conserved sequence at D22S134. Although no cDNAs have yet been isolated, genomic sequencing shows a short open reading frame with weak similarity to collagen proteins.

Conotruncal anomaly face syndrome is associated with a deletion within chromosome 22q11.

The conotruncal anomaly face syndrome was described in a Japanese publication in 1976 and comprises dysmorphic facial appearance and outflow tract defects of the heart. The authors subsequently noted similarities to Shprintzen syndrome and DiGeorge syndrome. Chromosome analysis in five cases did not show a deletion at high resolution, but fluorescent in situ hybridisation using probe DO832 showed a deletion within chromosome 22q11 in all cases.

Isolation of a gene expressed during early embryogenesis from the region of 22q11 commonly deleted in DiGeorge syndrome.

DiGeorge syndrome (DGS) is one of several syndromes associated with deletions within the proximal long-arm of chromosome 22. The region of chromosome 22q11 responsible for the haploinsufficiency syndromes (the DiGeorge Critical Region or DGCR) has been mapped using RFLPs, quantitative Southern blotting and FISH. Similar deletions are seen in the velo-cardio-facial syndrome (VCFS) and familial congenital heart defects. It is not known whether the phenotypic spectrum is the result of the hemizygosity of one gene or whether it is a consequence of contiguous genes being deleted. However, the majority of patients have a large (> = 2Mb deletion). In this paper we report the isolation of a gene, lab name T10, encoding a serine/threonine rich protein of unknown function which maps to the commonly deleted region of chromosome 22q11. Studies in the mouse indicate that it maps to MMU16 and is expressed during early embryogenesis. Although not mapping within the shortest region of overlap for DGS/VCFS, and therefore not the major gene involved in DGS, the expression pattern suggests that this gene may be involved in modifying the haploinsufficient phenotype of hemizygous patients.

Molecular cytogenetic characterization of the DiGeorge syndrome region using fluorescence in situ hybridization.

DiGeorge syndrome (DGS) is a developmental defect characterized by cardiac defects, facial dysmorphism, and mental retardation. Several studies have described a critical region for DGS at 22q11, within which the majority of DGS patients have deletions. We have isolated nine cosmid and three YAC clones using previously described and newly isolated probes that have been shown to be deleted in many DGS patients. Using fluorescence in situ hybridization and digital imaging, we have mapped and ordered these clones relative to the breakpoints of two balanced translocations at 22q11 (one in a DGS patient and one in the unaffected parent of a DGS child). Our data indicate that the breakpoint in the unaffected individual distally limits the DGS critical region (defined as the smallest region of overlap), while proximally the region is limited by repeat-rich DNA. The critical region includes the balanced translocation breakpoint of the DGS patient that presumably disrupts the gene causing this syndrome.

Molecular genetic study of the frequency of monosomy 22q11 in DiGeorge syndrome.

It is well established that DiGeorge syndrome (DGS) may be associated with monosomy of 22q11-pter. More recently, DNA probes have been used to detect hemizygosity for this region in patients with no visible karyotypic abnormality. However, DGS has also been described in cases where the cytogenetic abnormality does not involve 22q11; for instance, four cases of 10p- have been reported. In this study we have prospectively analyzed patients, by using DNA markers from 22q11, to assess the frequency of 22q11 rearrangements in DGS. Twenty-one of 22 cases had demonstrable hemizygosity for 22q11. Cytogenetic analysis had identified interstitial deletion in 6 of 16 cases tested; in 6 other cases no karyotype was available. When these results are combined with those from our previous studies, 33 of 35 DGS patients had chromosome 22q11 deletions detectable by DNA probes.

Loss of heterozygosity for chromosome region 11p15 in Wilms' tumours is not related to HRAS gene transforming mutations.

Although a candidate Wilms' tumour gene--WT1--has been identified in chromosome region 11p13, there is strong evidence from loss of heterozygosity studies suggesting that a second relevant gene is present in region 11p15. The Harvey-Ras proto-oncogene also lies in this region. In other types of tumours mutations in RAS genes have been associated with the development and/or progression of a number of tumour types. We therefore analysed the sequence of the Ras oncogene for possible mutations in six Wilms' tumours showing loss of heterozygosity for chromosome region 11p15. No tumour analysed showed HRAS sequence mutations. We conclude that loss of heterozygosity at 11p15 does not implicate HRAS mutations in the molecular pathogenesis of Wilms' tumour.

Structural rearrangements of the WT1 gene in Wilms' tumour cells.

We have analysed 55 Wilms' tumour DNAs using the cDNA from the candidate Wilms' predisposition gene, WT1. One tumour, GOS 129, shows a partial homozygous deletion involving only the 3'-most exon of the gene. An adjacent 3' DNA sequence, J7-18, which lies on the same NotI fragment as WT1, is present in GOS 129. Thus, this partial deletion does not extend to the adjacent unmethylated 3' HTF island. These data support the candidature of WT1 as a Wilms' predisposition gene. Tumour GOS 129 has become homozygous as a result of a mitotic recombination event proximal to WT1. Three other tumours showed abnormally sized bands on Southern blot analysis which appear to reflect internal heterozygous rearrangements involving the 5' end of the gene. One of these tumours was from a bilaterally-affected patient and the other 3 were from stage III or IV tumours.

Molecular analysis of chromosome region 11p13 in patients with Drash syndrome.

The association of nephropathy, Wilms' tumour and genital abnormalities is known as Drash syndrome. Two of these features are also seen in the WAGR (Wilms' tumour, aniridia, genito-urinary abnormalities, mental retardation) complex, known to be associated with deletions of chromosome region 11p13. We have carried out karyotypic and molecular studies in 10 Drash patients, 5 males and 5 females. All the males had a 46XY karyotype as did 3/5 of the phenotypic females, the other two having a 46XX karyotype. One of the 46XX females also had a deletion of region 11p13-p12, the only detectable autosomal chromosome abnormality in any of the patients studied. Lymphoblastoid cell lines were prepared from 6 of the Drash patients and were used in dosage studies using a variety of DNA probes from the 11p13 region. There was no evidence of microdeletions in any patient with a normal karyotype. Because of the 46XY karyotype in phenotypic females, selected X and Y chromosome loci were analysed and all found to be normal. Although Drash syndrome is likely to be of genetic origin, there are no readily detected deletions within the 11p13 region.

Preferential loss of maternal alleles in sporadic Wilms' tumour.

Loss of heterozygosity at loci on the short arm of chromosome 11 has been reported in 31% (11/38) of Wilms' tumours in our series. Lymphoblastoid cell lines were prepared from the parents of 10/11 of the patients showing allele loss in their tumours. In 9 of the cases, where the parental origin of the alleles could be followed, it was the paternal alleles which were retained in the tumour. This preferential loss of the maternal alleles implies a role for genomic imprinting in the pathogenesis of Wilms' tumour.

Loss of heterozygosity in Wilms' tumour involves two distinct regions of chromosome 11.

Pairs of tumour and normal DNA samples from 38 Wilms' tumour patients have been investigated for loss of heterozygosity using 12 probes from chromosome 11. Allele loss was detected in only 11 cases (31%). Densitometric analysis showed that allele loss was not due to non-disjunction or hemizygous deletion, but rather to mitotic recombination or non-disjunction plus reduplication. Although the development of homozygosity sometimes involved the whole of the short arm of chromosome 11, in a few tumours allele loss was restricted to band 11p15 or 11p13 and distal sequences. This suggests mutations in two distinct regions play an important role in Wilms' tumorigenesis. There was no apparent correlation between loss of heterozygosity and tumour stage, age of presentation, or prior exposure to chemotherapy.