Biomedical subjects

Klaus W Kjaer

Publications and source records attributed to Klaus W Kjaer.

11 recordsLinked to original sources

PubMed2006

Delineation of the ADULT syndrome phenotype due to arginine 298 mutations of the p63 gene.

The ADULT syndrome (Acro-Dermato-Ungual-Lacrimal-Tooth, OMIM 103285) is a rare ectodermal dysplasia associated with limb malformations and caused by heterozygous mutations in p63. ADULT syndrome has clinical overlap with other p63 mutation syndromes, such as EEC (OMIM 604292), LMS (OMIM 603543), AEC (106260), RHS (129400) and SHFM4 (605289). ADULT syndrome characteristics are ectrodactyly, ectodermal dysplasia, mammary gland hypoplasia and normal lip and palate. The latter findings allow differentiation from EEC syndrome. LMS differs by milder ectodermal involvement. Here, we report three new unrelated ADULT syndrome families, all with mutations of arginine 298. On basis of 16 patients in five families with R298 mutation, we delineate the ADULT syndrome phenotype. In addition, we have documented a gain-of-function effect on the dNp63gamma isoform caused by this mutation. We discuss the possible relevance of oral squamous cell carcinoma in one patient, who carries this p63 germline mutation.

Abnormalities, Multiple↗

PubMed2006

Germline LEMD3 mutations are rare in sporadic patients with isolated melorheostosis.

To further explore the allelic heterogeneity within the group of LEMD3-related disorders, we have screened a larger series of patients including 5 probands with osteopoikilosis or Buschke-Ollendorff syndrome (BOS), 2 families with the co-occurrence of melorheostosis and BOS, and 12 unrelated patients with isolated melorheostosis. Seven novel LEMD3 mutations were identified, all predicted to result in loss-of-function of the protein. We confirm that loss-of-function mutations in the LEMD3 gene can result in either osteopoikilosis or BOS. However, LEMD3 germline mutations were only found in two melorheostosis patients belonging to a different BOS family and one sporadic patient with melorheostosis. The additional presence of osteopoikilosis lesions in these patients seemed to distinguish them from the group of sporadic melorheostosis patients where no germline LEMD3 mutation was identified. Somatic mosaicism for a LEMD3 mutation in the latter group was also not observed, and therefore we must conclude that the genetic defect in the majority of sporadic and isolated melorheostosis remains unknown.

Alleles↗

PubMed2005

A 72-year-old Danish puzzle resolved--comparative analysis of phenotypes in families with different-sized HOXD13 polyalanine expansions.

A phenotype-genotype correlation was previously described for carriers of different sized of polyalanine expansions in HOXD13. We report on a detailed comparison of 55 members (approximately 220 limbs) from 4 Danish families with duplications of 21 or 27 bp, expanding the polyalanine repeat from 15 to 22 and 24 residues, respectively. Two of these were previously described by Danish pioneers of human genetics, Tage Kemp and Oluf Thomsen. A clinical score was assigned to each limb based on manifestations assumed to represent different degrees of a duplication defect in hand rays 3-4 and foot rays 4-5. The length of metacarpals and phalangeal bones in rays 1, 2, and 5 was measured on hand radiographs and converted to Z-scores. The relative difference between corresponding right and left bones and directional, total, and fluctuating asymmetry was calculated for each individual. All of these parameters were compared between carriers of the +9 alanine expansion, the +7 alanine expansion, and non-mutation carriers with affected parents from the two families. Upper limb scores and the rate of abnormal bones (>2SD) were significantly higher in the first group than in the others. The first metacarpal and the middle phalanx of the little finger were significantly shorter, and the proximal phalanx of the index finger was significantly longer in this group than in the others. An increased level of total and fluctuating asymmetry was observed in long expansion carriers. Thus, our data have added evidence to the phenotype-genotype correlation previously reported, which was further extended to include lesser involvement of bones in ray 1, 2, and 5.

Base Sequence↗

PubMed2005

Male-to-male transmission in Laurin-Sandrow syndrome and exclusion of RARB and RARG.

We report on a father and a son with nasal and limb defects characteristic of Laurin-Sandrow syndrome (LSS) excluding for the first time X-linked inheritance in this rare condition. Based on a search for genes expressed late during nose formation and early in limb formation we identified retinoic acid receptor B (RARB) and retinoic acid receptor G (RARG) as possible candidate genes and sequenced bidirectionally including all exons and intron-exon bounders. We identified a single nucleotide substitution in intron 2 of RARB, which is conserved in human, chimp, dog, mouse, rat, and chicken. However, it was located 83 bp from exon 2, suggesting it is a rare polymorphism which does not account for the phenotype. No other mutations were found. This suggests that another yet unknown gene is responsible for the condition.

Abnormalities, Multiple↗

PubMed2005

Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2.

Here we describe 2 mutations in growth and differentiation factor 5 (GDF5) that alter receptor-binding affinities. They cause brachydactyly type A2 (L441P) and symphalangism (R438L), conditions previously associated with mutations in the GDF5 receptor bone morphogenetic protein receptor type 1b (BMPR1B) and the BMP antagonist NOGGIN, respectively. We expressed the mutant proteins in limb bud micromass culture and treated ATDC5 and C2C12 cells with recombinant GDF5. Our results indicated that the L441P mutant is almost inactive. The R438L mutant, in contrast, showed increased biological activity when compared with WT GDF5. Biosensor interaction analyses revealed loss of binding to BMPR1A and BMPR1B ectodomains for the L441P mutant, whereas the R438L mutant showed normal binding to BMPR1B but increased binding to BMPR1A, the receptor normally activated by BMP2. The binding to NOGGIN was normal for both mutants. Thus, the brachydactyly type A2 phenotype (L441P) is caused by inhibition of the ligand-receptor interaction, whereas the symphalangism phenotype (R438L) is caused by a loss of receptor-binding specificity, resulting in a gain of function by the acquisition of BMP2-like properties. The presented experiments have identified some of the main determinants of GDF5 receptor-binding specificity in vivo and open new prospects for generating antagonists and superagonists of GDF5.

Amino Acid Sequence↗

PubMed2005

Sensorineural deafness, abnormal genitalia, synostosis of metacarpals and metatarsals 4 and 5, and mental retardation: description of a second patient and exclusion of HOXD13.

In 1988 Pfeiffer and Kapferer reported on a patient with sensorineural deafness, psychomotor delay, hypospadias, cerebral manifestations, and bilateral synostosis of the 4th and 5th metacarpals and metatarsals. Synostosis of the 4th and 5th metacarpals and metatarsals is a very rare defect that has been described as an isolated Mendelian defect, as part of multiple congenital anomaly (MCA) patterns, and in different syndromes. Among a total of 2,023,155 liveborn infants in the Spanish Collaborative Study of Congenital Malformations (ECEMC), we observed only two cases with this type of metacarpal fusion, for a frequency of 1/1,011,577. One had the isolated defect, and the other one that we are describing here, had an MCA pattern similar to that described by Pfeiffer and Kapferer [1988]. We tested HOXD13 but did not find any mutations in exons and intron-exon boundaries. To our knowledge this case is the second one reported with this syndrome.

Abnormalities, Multiple↗

PubMed2005

Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome.

Warburg Micro syndrome (WARBM1) is a severe autosomal recessive disorder characterized by developmental abnormalities of the eye and central nervous system and by microgenitalia. We identified homozygous inactivating mutations in RAB3GAP, encoding RAB3 GTPase activating protein, a key regulator of the Rab3 pathway implicated in exocytic release of neurotransmitters and hormones, in 12 families with Micro syndrome. We hypothesize that the underlying pathogenesis of Micro syndrome is a failure of exocytic release of ocular and neurodevelopmental trophic factors.

Catalytic Domain↗

PubMed2005

Immunohistochemical expression of p63 in human prenatal tooth primordia.

The aim of this study was to investigate the expression of the p63 gene in normal human tooth buds at different gestational stages. This is the first detailed study of p63 expression in normal human prenatal tooth primordia. The material consisted of sections of the midaxial tissue block from the cranial base of three human fetuses of gestational ages (GA) 11, 15, and 21 weeks. The sections included tooth primordia representing cap stages and bell stages of human tooth morphogenesis. In the present study, immunostaining was carried out using the primary antibody, monoclonal mouse anti human p63 protein, clone 4A4. The sections were counterstained with hematoxylin Mayer. p63 immunoreactivity was identified by microscopy. The study showed a positive reaction of p63 in both the cap stage and the bell stage. In both stages, positivity was observed in the cells of the oral mucosa, the inner and outer enamel epithelium, and in the primary and secondary dental lamina. In the early cap stage, there is a strong positive reaction to p63 in the enamel knot, but not in the late cap stage. We suggest that p63 may have an important regulatory function in the enamel knot.

DNA-Binding Proteins↗

PubMed2004

Novel Connexin 43 (GJA1) mutation causes oculo-dento-digital dysplasia with curly hair.

Oculo-dento-digital dysplasia (ODDD) [OMIM 164200] is a rare autosomal dominant pleiotropic disorder comprising ocular, craniofacial, and digital anomalies, caused by mutations in the gap junction alpha-1 gene (GJA1 or Connexin 43 (CX43)) [Paznekas et al., 2003]. In a Danish family affected over five generations, we found a novel mutation, 286G --> A, resulting in Val96Met. We provide an easy method for mutation detection by use of the restriction enzyme Nde1 and discuss possible pathogenetic mechanisms, arguing that loss of function cannot be excluded. This is the second article reporting ODDD mutations.

Abnormalities, Multiple↗

PubMed2003

Sirenomelia sequence according to the distance between the first sacral vertebra and the ilia.

The development of the iliac bones and lower limbs are parallel processes depending on the normal ontogeny of the caudal blastema [O'Rahilly and Müller, 1989; Opitz, 1993; Opitz et al., 2000]. We hypothesized that the pathogenetic mechanisms leading to fused lower limbs would in parallel displace the ilia caudally and medially and that the degree of this displacement might correlate with the severity of the iliac and lower limb defects. Thus the purpose of the study was to test this hypothesis in a sample of 12 sirenomelic fetuses. The fetuses GA 16-39 weeks, spontaneously or therapeutically aborted, were radiographed in the frontal projection as part of a requested autopsy. From each radiograph, a line was drawn connecting the most cranial part or the two ilia. After that the distance was measured vertically between this line and the most cranial part of the first sacral vertebral body (iliac-sacral distance (ISD)). A second distance was measured horizontally between the most lateral part of the two iliae (bi-iliac distance (BD)). As a result, ISD correlates with the iliac/femur phenotype. Separate ilia and femora occur only in cases with normal ISD. Fused ilia or femora or both are seen only in fetuses with mildly increased ISD, whereas a single iliac bone and femur occur only in cases with greatly increased ISD. The increase of the ISD does not correlate with the severity of more distal limb involvement. There was a correlation between the ISD and the BD values; the higher the ISD, the shorter the BD. Based on these findings, we propose an extended classification of Sirenomelia to be tested by other researchers.

Ectromelia↗

PubMed2002

Limb anomalies: Developmental and evolutionary aspects.

In this review we describe the developmental mechanisms involved in the making of a limb, by focusing on the nature and types of interactions of the molecules that play a part in the regulation of limb patterning and characterizing clinical conditions that are known to result from the abnormal function of these molecules. The latter subject is divided into sections dealing with syndromal and nonsyndromal deficiencies, polydactylies, and brachydactylies. Conditions caused by mutations in homeobox genes and fibroblast growth factors and their receptor genes are listed separately. Since the process of limb development has been conserved for more than 300 millions years, with all the necessary adaptive modifications occurring throughout evolution, we also take into consideration the evolutionary aspects of limb development in terms of genetic repertoire, molecular pathways, and morphogenetic events.

Animals↗