A novel point mutation A170P in the SHOX gene defines impaired nuclear translocation as a molecular cause for Léri-Weill dyschondrosteosis and Langer dysplasia.
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Adult↗
Biomedical subjects
G Rappold
Publications and source records attributed to G Rappold.
Position effect on PLP1 may cause a subset of Pelizaeus-Merzbacher disease symptoms.
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Ataxia↗
Expression of SHOX in human fetal and childhood growth plate.
Abnormalities in the growth plate may lead to short stature and skeletal deformity including Leri Weil syndrome, which has been shown to result from deletions or mutations in the SHOX gene, a homeobox gene located at the pseudoautosomal region of the X and Y chromosome. We studied the expression of SHOX protein, by immunohistochemistry, in human fetal and childhood growth plates and mRNA by in situ hybridization in childhood normal and Leri Weil growth plate. SHOX protein was found in reserve, proliferative, and hypertrophic zones of fetal growth plate from 12 wk to term and childhood control and Leri Weil growth plates. The pattern of immunostaining in the proliferative zone of childhood growth plate was patchy, with more intense uniform immunostaining in the hypertrophic zone. In situ hybridization studies of childhood growth plate demonstrated SHOX mRNA expression throughout the growth plate. No difference in the pattern of SHOX protein or mRNA expression was seen between the control and Leri Weil growth plate. These findings suggest that SHOX plays a role in chondrocyte function in the growth plate.
Adolescent↗
P1 SHOX and limb development.
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Journal Article↗
[Carpal injuries associated with distal radius fractures. Diagnosis and therapy].
The frequency of carpal injuries associated with distal radius fractures is often underestimated. Diagnosis of such lesions can be difficult. Important diagnostic steps include conventional X-rays, cinematography of the wrist, MRI, and arthroscopy. Different procedures such as wrist arthrography and CT are of secondary value. An early diagnosis of ligament injuries and instabilities can be obtained through cinematographic examination, whereas injuries to the TFCC are mainly diagnosed by MRI. Arthroscopy provides exact diagnosis as well as therapy, including arthroscopically controlled reposition of centrally depressed fragments of the articular surface of the radius and even treatment of TFCC lesions.
Arthroscopy↗
[High-pressure injection injuries of the hand. Pathogenesis, problems and therapy].
Summary.High-pressure injection injuries are rare and the extent of tissue damage is often underestimated. They usually have devastating effects on tissues and result in poor functional outcome of the involved hand. The severity of these injuries is related to the nature, pressure, volume and toxicity of the injected substance. The major problem of this injury is a toxic edema followed by ischemia, causing a gangrene of the involved finger, which may require amputation. The pathogenesis is characterized by different, but often synchronous onsets, leading to an apparent chain of events that occur once the material has been injected. Increase of pressure within the closed space leads to tamponade, intravascular thrombosis and spasm of vessels create circulatory embarrassment, a chemical irritation provokes an acute inflammation. Three stages of progress are described. Timing is an important factor influencing the results. An early, wide decompression and aggressive debridement with complete removal of foreign substances and necrosectomy is recommended in the acute stage and will improve prognosis and outcome. Open wound treatment and second-look operations during the intermediate stage are followed by secondary wound closure with local or free flaps, if necessary. We emphasize the role of early active motion during this time. Reconstructive surgery is reserved for the late stage.43 patients were treated surgically in our department over the last 28 years (1972 to 2000). 12 of them (28 %) required amputation at different levels of the involved finger. Only nine patients healed without any functional loss. Most frequent injuries were of the paint or paint-solvent and grease-gun type.
Accidents, Occupational↗
Differential divergence of three human pseudoautosomal genes and their mouse homologs: implications for sex chromosome evolution.
The human pseudoautosomal region 1 (PAR1) is essential for meiotic pairing and recombination, and its deletion causes male sterility. Comparative studies of human and mouse pseudoautosomal genes are valuable in charting the evolution of this interesting region, but have been limited by the paucity of genes conserved between the two species. We have cloned a novel human PAR1 gene, DHRSXY, encoding an oxidoreductase of the short-chain dehydrogenase/reductase family, and isolated a mouse ortholog Dhrsxy. We also searched for mouse homologs of recently reported PGPL and TRAMP genes that flank it within PAR1. We recovered a highly conserved mouse ortholog of PGPL by cross-hybridization, but found no mouse homolog of TRAMP. Like Csf2ra and Il3ra, both mouse homologs are autosomal; Pgpl on chromosome 5, and Dhrsxy subtelomeric on chromosome 4. TRAMP, like the human genes within or near PAR1, is probably very divergent or absent in the mouse genome. We interpret the rapid divergence and loss of pseudoautosomal genes in terms of a model of selection for the concentration of repetitive recombinogenic sequences that predispose to high recombination and translocation.
Amino Acid Sequence↗
Growth hormone and gonadotropin-releasing hormone analog therapy in haploinsufficiency of SHOX.
We report on GH (0.5 IU or 0.17 mg/kg/week) and GnRH analog (GnRHa, 60 microg/kg, every 4 weeks) therapy in SHOX haploinsufficiency. Case 1 was a 46,XY boy with microdeletion of the Y chromosomal pseudoautosomal region. At 7 years of age, he exhibited short stature (-3.9 SD) with a reduced growth rate (3.8 cm/year), short 4th metacarpals, and mild Madelung deformity. GH therapy resulted in a marked increase in height velocity (10.7 cm/year in the first year). Case 2 was a 46,XX girl with a heterozygous nonsense mutation of SHOX (C674T). At 6 years of age, she presented with short stature (-3.3 SD) with a low height velocity (4.0 cm/year). GH therapy caused a moderate increase in height velocity (6.6 cm/year in the first year and 6.0 cm/year in the second year) before puberty. Because of breast development, she received GnRHa from 9 8/12 years of age. At 10 10/12 years of age, she had mild shortening and borderline curvature of radius. Case 3 was a girl with a 46,X,der(X)t(X;2)(p22.3;p21) karyotype. She was treated with GH from 6 to 14 years of age, and also with GnRHa from 12 to 15 years of age. Her height remained around mean -4 SD, with no discernible alteration of height velocity. At 17 years of age, she had short stature (-4.1 SD), bilateral cubitus valgus, Madelung deformity, and full breast development. The results suggest that GH therapy may have variable statural effects in SHOX haploinsufficiency as in most disorders including Turner syndrome, and that GnRHa therapy after pubertal entry may be insufficient to prevent the development of skeletal lesions such as Madelung deformity.
Body Height↗
Structural analysis of a rare rearranged Y chromosome and its bearing on genotype-phenotype correlation.
We report on a 9-year-old boy with a rare rearranged Y chromosome and borderline short stature (-2.0 SD). Standard metaphase chromosome analysis indicated a 46,X,i(Y)(q1O) karyotype, but high resolution G-banding showed an asymmetric band pattern for the rearranged Y chromosome. FISH and DNA studies for a total of 15 different Y chromosomal loci or regions showed that the rearranged Y chromosome was accompanied by: 1) a partial deletion of the short arm pseudoautosomal region (PAR1) involving SHOX, with the breakpoint distal to DXYS85; and 2) a partial duplication of Yq, with the breakpoint proximal to DAZ. The karyotype was determined as 46,X,?i(Y)(q1O).ish der(Y)(Yqter--> Yp11.3::Yq11.2-->Yqter)(DAZ++,DYZ3+,SRY +, SHOX-). The X chromosome and the autosomes were normal. The results suggest that haploinsufficiency of SHOX is primarily responsible for the borderline short stature, and that the deletion of the PAR1 may result in spermatogenic failure due to defective X-Y pairing and recombination in the PAR1.
Child↗
Mosaic rearrangement of chromosome 18: characterization by FISH mapping and DNA studies shows trisomy 18p and monosomy 18p both of paternal origin.
Structural abnormalities of chromosome 18p mainly consist of isochromosomes of the short arm, which result in tetrasomy 18p. Trisomy 18p is much rarer, and less well characterized. We report on a 12-year-old girl with minor facial anomalies, delayed development, abnormal hands, atopic dermatitis, and hearing loss. She was mosaic for two abnormal cell lines in peripheral blood. In 90% of cells, a dicentric chromosome with duplication of the whole short arm of chromosome 18 resulted in trisomy 18p; 10% of cells had monosomy 18p, arising from a t(14;18)(p11;q11). FISH mapping, with multiple region specific and locus specific probes from the short and long arm of chromosome 18, showed that the structure of the dicentric chromosome 18 was 18pter-->18q23::18q11-->18pter. DNA polymorphisms for chromosome 18 showed that the abnormalities of chromosome 18 were paternal in origin. Combining all results, we could link the trisomy 18p and monosomy 18p to a common origin via a complex series of events in an early mitosis.
Abnormalities, Multiple↗
Evidence for heterogeneity in recombination in the human pseudoautosomal region: high resolution analysis by sperm typing and radiation-hybrid mapping.
Accurate genetic and physical maps for the human pseudoautosomal region were constructed by use of sperm typing and high-resolution radiation-hybrid mapping. PCR analysis of 1,912 sperm was done with a manual, single-sperm isolation method. Data on four donors show highly significant linkage heterogeneity among individuals. The most significant difference was observed in a marker interval located in the middle of the Xp/Yp pseudoautosomal region, where one donor showed a particularly high recombination fraction. Longitudinal models were fitted to the data to test whether linkage heterogeneity among donors was significant for multiple intervals across the region. The results indicated that increased recombination in particular individuals and regions is compensated for by reduced recombination in neighboring intervals. To investigate correspondence between physical and genetic distances within the region, we constructed a high-resolution radiation-hybrid map containing 29 markers. The recombination fraction per unit of physical distance varies between regions ranging from 13- to 70-fold greater than the genome-average rate.
Adult↗
Elevated DNA sequence diversity in the genomic region of the phosphatase PPP2R3L gene in the human pseudoautosomal region.
The evolution, inheritance and recombination rate of genes located in the pseudoautosomal region 1 (PAR1) is exceptional within the human genome. Pseudoautosomal genes are identical on X and Y chromosomes and are not inherited in a sex linked manner. Due to an obligatory recombination event in male meiosis, pseudoautosomal genes are exchanged frequently between X and Y chromosomes. During the isolation, characterization and sequencing of a novel gene PPP2R3L, which was classified by sequence homology as a novel member of the protein phosphatase regulatory subunit families, it became apparent that cosmids of different origin harboring this gene are highly polymorphic between individuals, both at the nucleotide level and in the number.
Amino Acid Sequence↗
Characterization of the rat, mouse, and human genes of growth/differentiation factor-15/macrophage inhibiting cytokine-1 (GDF-15/MIC-1).
We have isolated the rat, mouse and human genes of a distant member of the TGF-beta superfamily, growth/differentiation factor-15/macrophage inhibiting cytokine-1 (GDF-15/MIC-1) by screening of genomic libraries. All three genes are composed of two exons, and contain one single intron that interrupts the coding sequences at identical positions within the prepro-domain of the corresponding proteins. The predicted proteins contain the structural hallmarks of members of the TGF-beta superfamily, including the seven conserved carboxy-terminal cysteine residues that form the cystine knot. The orthologous molecules show the lowest sequence conservation of all members of the TGF-beta superfamily. RT-PCR reveals an abundant expression of GDF-15/MIC-1 mRNA in numerous embryonic and adult organs and tissues. Promoter analysis of the rat promoter indicates the presence of multiple regulatory elements, including a TATA-like sequence as well as several SP1, AP-1 and AP-2 sites. Deletion analysis suggests that a 350 bp region upstream of the start of the open reading frame appears to be the most important for regulation of transcription.
Amino Acid Motifs↗
Léri-Weill syndrome as part of a contiguous gene syndrome at Xp22.3.
We report on a mother and her 5-year old son, both with a terminal deletion of the short arm of the X chromosome. By molecular genetic analysis the breakpoint was located distal to steroid sulfatase gene. The boy manifested, due to nullisomy of this region, short stature (SHOX), chondrodysplasia punctata (ARSE), and mental retardation (putative mental retardation gene MRX 49). Short stature is present in mother and son, but both also had bilateral Madelung deformity, a key finding in the Léri-Weill syndrome. We discuss the phenotype in relationship to hitherto published cases with chromosomal aberrations and contiguous gene syndromes of Xp22.3.
Abnormalities, Multiple↗
Physical assignment of the bovine MHC class IIa and class IIb genes.
Screening of a bovine yeast artificial chromosome (YAC) library revealed two clones which contain most of the class II genes of the major histocompatibility complex (MHC) known to date. The YACs were mapped by fluorescence in situ hybridization (FISH) and characterized for the class II genes they contain. We found that the classic class II genes BoLA- DQA, -DQB, -DRA, and -DRB3 are located at BTA 23q21 and the non-classic class II genes DYA, DIB, LMP2, LMP7, TAP2, BoLA-DOB, -DMA, -DMB, and -DNA are located at BTA 23q12-->q13. These two different mapping locations confirm and extend previous findings of a gross physical distance between classic and non-classic MHC class II genes in cattle.
Animals↗
A novel pseudoautosomal gene encoding a putative GTP-binding protein resides in the vicinity of the Xp/Yp telomere.
We report the cloning of a novel Xp/Yp pseudoautosomal gene called PGPL , and demonstrate that PGPL , like other pseudoautosomal genes, escapes X inactivation and has a functional homologue on the Y chromosome. This gene is expressed in all the tissues examined and is highly conserved across several species. The PGPL gene encodes a protein of 442 amino acids and shows the consensus sequences of a series of motifs of the GTP-binding protein domain. Using fluorescence in situ hybridization analysis on normal males and on patients with rearrangements in the pseudoautosomal region, the gene was localized within 500 kb of the telomere. Further refinement using a cosmid contig of the region places this novel gene within 80-110 kb of the telomere, making this the most telomeric gene on the short arms of the sex chromosomes.
Amino Acid Sequence↗
High-resolution fluorescence in situ hybridization of human Y-linked genes on released chromatin.
Genes within the differential region of the human Y chromosome do not recombine, and therefore the determination of their location depends on physical mapping. Yeast artificial chromosome (YAC) contigs spanning the euchromatic region of the human Y have become a powerful tool for the generation of an overlapping clone map. With this approach, however, complete physical mapping is difficult in Y euchromatic regions that are rich in repetitive sequences. We have, therefore, made use of the fluorescence in situ hybridization technique as an alternative strategy for physically mapping the PRKY and AMELY genes as well as the TSPY, RBM and DAZ gene families to human Y chromosomes in prometaphase and to extended Y chromatin in interphase. From our results, the following order of gene sequences in interval 3 of the short arm of the human Y chromosome is suggested: TSPY major with few RBM sequences interspersed-PRKY-AMELY-TSPY minor with few RBM sequences interspersed-cen. On the long arm, RBM sequences appear to be distributed over wide regions of intervals 5 and 6 with few TSPY sequences interspersed. Distal to an RBM signal cluster, a large cluster of DAZ signals is located with only a few DAZ and RBM signals overlapping in between the two clusters.
Cell Cycle Proteins↗
Comparative mapping of Xp22 genes in hominoids--evolutionary linear instability of their Y homologues.
Several genes located within or proximal to the human PAR in Xp22 have homologues on the Y chromosome and escape, or partly escape, inactivation. To study the evolution of Xp22 genes and their Y homologues, we applied multicolour fluorescence in situ hybridization (FISH) to comparatively map DNA probes for the genes ANT3, XG, ARSD, ARSE (CDPX), PRK, STS, KAL and AMEL to prometaphase chromosomes of the human species and hominoid apes. We demonstrate that the genes residing proximal to the PAR have a highly conserved order on the higher primate X chromosomes but show considerable rearrangements on the Y chromosomes of hominoids. These rearrangements cannot be traced back to a simple model involving only a single or a few evolutionary events. The linear instability of the Y chromosomes gives some insight into the evolutionary isolation of large parts of the Y chromosomes and thus might reflect the isolated evolutionary history of the primate species over millions of years.
Animals↗