Thirty years old, white man, presented with congenital reddish slightly thicken facial lesion with scattered nodules on the left side, to dermatology clinic, seeking a cosmetic alleviate. He has no other complains (i.e., no bleeding, no headache, no eye pain or visual impairment). Also, the patient has noticed that the lesion slightly decreased with aging. Family history (FH) was irrelevant.

Hyperkeratotic capillary-venous malformations (HCCVMs) are rare cutaneous lesions that occur in a small subgroup of patients with cerebral capillary malformation (CCM). CCMs cause neurological problems that range from headaches to life-threatening intracranial bleeding. CCMs and HCCVMs have a similar histopathological appearance of dilated capillary-venous channels. Genetic linkage of inherited CCMs has been established to three chromosomal loci, 3q25. 2-27, 7p13-15 and 7q21-22. The first mutations were identified in the CCM1 gene (located on 7q21-22), which encodes KRIT1 protein (KREV1 interaction trapped 1), presumably a membrane-bound protein with signalling activity. Although KRIT1 is known to interact with KREV1/RAP1A, a Ras-family GTPase, the exact function of KRIT1 in the formation of cerebral capillaries and veins is poorly understood. In this study, we screened five families with CCM for mutations in the KRIT1 gene. In one of the families, CCMs co-segregated with HCCVMs. We identified a KRIT1Delta(G103)mutation in this family, suggesting that this rare form of the condition is also caused by mutations in the CCM1 gene and that KRIT1 is probably important for cutaneous vasculature. Interestingly, this deletion introduces the earliest stop codon among identified mutations, suggesting a possible correlation between the molecular alteration and the cutaneous phenotype. Another novel mutation, KRIT1(IVS2+2(T-->C)), was found in a family with only cerebral capillary-venous malformations.

Capillary malformation (CM; 'port-wine stain'), is a common vascular malformation affecting cutaneous capillary vessels in 0.3% of newborns. Increased incidence of lesions in first-degree relatives of these patients and several reported familial cases suggest that genetic factors may play a role in the pathogenesis of CM. We report the first genome-wide linkage analysis of familial CM. In the non-parametric linkage analysis, strong evidence of linkage (peak Z-score 6.72, P-value 0.000136) was obtained in an interval of 69 cM between markers D5S407 and D5S2098, corresponding to 5q11 -5q23. Parametric linkage analysis gave a maximum combined HLOD score of 4.84 (a-value 0.67) at marker D5S2044 on 5q15, and analysis using only the linked families, defined a smaller, statistically significant locus CMC1 of 23 cM (peak LOD score 7.22) between markers D5S1962 and D5S652 corresponding to 5q13 -5q15. Interesting candidate genes implicated in vascular and neural development, such as MEF2C, RASA1, and THBS4, are in this locus.

Overlapping genomic clones covering the 7.2 kb mouse alpha 1(X) collagen gene, 0.86 kb of promoter and 1.25 kb of 3'-flanking sequences were isolated from two genomic libraries and characterized by nucleotide sequencing. Typical features of the gene include a unique three-exon structure, similar to that in the chick gene, with the entire triple-helical domain of 463 amino acids coded by a single large exon. The highest degree of amino acid and nucleotide sequence conservation was seen in the coding region for the collagenous and C-terminal non-collagenous domains between the mouse and known chick, bovine and human collagen type X sequences. More divergence between the sequences occurred in the N-terminal non-collagenous domain. Similarity between the mammalian collagen X sequences extended into the 3'-untranslated sequence, particularly near the polyadenylation site. The promoter of the mouse collagen X gene was found to contain two TATAA boxes 159 bp apart; primer extension analyses of the transcription start site revealed that both were functional. The promoter has an unusual structure with a very low G + C content of 28% between positions -220 and -1 of the upstream transcription start site. Northern and in situ hybridization analyses confirmed that the expression of the alpha 1(X) collagen gene is restricted to hypertrophic chondrocytes in tissues undergoing endochondral calcification. The detailed sequence information of the gene is useful for studies on the promoter activity of the gene and for generation of transgenic mice.

Objective. To perform a systematic study on the production and deposition of type X collagen in developing, aging, and osteoarthritic (OA) mouse articular cartilage.Methods. Immunohistochemistry was employed to define the distribution of type X collagen and Northern analyses to determine the messenger RNA levels as an indicator of the synthetic activity of the protein.Results. Type X collagen was observed in the epiphyseal and articular cartilage of mouse knee joints throughout development and growth. Type X collagen deposition in the transitional zone of articular cartilage became evident toward cessation of growth, at the age of 2-3 months. The most intense staining for type X collagen was limited to the tidemark, the border between uncalcified and calcified cartilage. Northern analysis confirmed that the type X collagen gene is also transcribed by articular cartilage chondrocytes. Intense immunostaining was observed in the areas of OA lesions, specifically, at sites of osteophyte formation and surface fibrillation, Type X collagen deposition was also seen in degenerating menisci.Conclusion. This study demonstrates that type X collagen is a natural component of mouse articular cartilage throughout development, growth, and aging. This finding and the deposition of type X collagen at sites of OA lesions suggest that type X collagen may have a role in providing structural support for articular cartilage.Maintenance of the integrity and shockabsorbing properties of hyaline cartilage at articular surfaces is of fundamental importance to vertebrate locomotion. Disruption of articular cartilage impairs these functions and leads to osteoarthritis (OA), a gradually progressing, disabling disease that affects a large and growing proportion of the elderly population throughout the world (1). OA has a heterogenous background, In a majority of cases, no obvious connection to a predisposing factor is seen, and the disease is still often regarded as an inevitable consequence of aging. Etiologic factors predisposing to OA include trauma, obcsity, and abnormal weight distribution at articular surfaces, as well as metabolic disturbances and minor mutations in genes coding for structural components of hyaline cartilage (2). The structural strength of hyaline cartilage is generally ascribed to a network of heterotypic collagen fibrils composed of types 11, TX, and XI collagens which entrap the large protcoglycan molcculcs, providing cartilage with resilience (3-5). A striking feature of adult articular cartilage is its remarkably poor regenerative capacity, particularly with respect to the production of new cartilage collagens (6,7).Another collagen, type X, has recently becn identified in adult human and porcine articular Cartilage, as well as at the articular surfaces in fetal rats (8). In adult canine articular cartilage, type X collagen was observed in the calcified zone in the pericellular matrix of chondrocytes (9). In OA cartilage, expression of type X collagen has been observed around proliferating and maturing chondrocyt...