Biomedical subjects

Astrid S Plomp

Publications and source records attributed to Astrid S Plomp.

4 recordsLinked to original sources

PubMed2006

ABCC6 and pseudoxanthoma elasticum.

ABCC6 belongs to the adenosine triphosphate-binding cassette (ABC) gene subfamily C. This protein family is involved in a large variety of physiological processes, such as signal transduction, protein secretion, drug and antibiotic resistance, and antigen presentation [Kool et al. (1999) 59:175-182; Borst and Elferink (2002) 71:537-592]. ABCC6 is primarily and highly expressed in the liver and kidney [Kool et al. (1999) 59:175-182; Bergen et al. (2000) 25:228-2231]. The precise physiological function and natural substrate(s) transported by ABCC6 are unknown, but the protein may be involved in active transport of intracellular compounds to the extracellular environment [Kool et al. (1999) 59:175-182] [Scheffer et al. (2002) 82:515-518]. Recently, it was shown that loss of function mutations in ABCC6 cause pseudoxanthoma elasticum (PXE) [Bergen et al. (2000) 25:228-2231; Le Saux et al. (2000) 25:223-227]. PXE is an autosomal recessively inherited multi-organ disorder [Goodman et al. (1963) 42:297-334; Lebwohl et al. (1994) 30:103-107]. PXE is primarily associated with the accumulation of mineralized and fragmented elastic fibers of the connective tissue in the skin [Neldner (1988) 6:1-159], Bruch's membrane in the retina [Hu et al. (2003) 48:424-438], and vessel walls [Kornet et al. (2004) 30:1041-1048]. PXE patients usually have skin lesions and breaks in Bruch's membrane of the retina (angioid streaks). Also, a variety of cardiovascular complications has been observed [Hu et al. (2003) 48:424-438]. Recently, a mouse model for PXE was created by targeted disruption of Abcc6 [Gorgels et al. (2005) 14:1763-1773; Klement et al. (2005) 25:8299-8310], which may be useful to elucidate the precise function of Abcc6 and to develop experimental therapies.

ATP-Binding Cassette Transporters↗

PubMed2006

Influence of mutation type on clinical expression of Leber hereditary optic neuropathy.

PURPOSE: The aim of this research was to determine the molecular factors of influence on the clinical expression of Leber hereditary optic neuropathy (LHON), which might aid in counseling LHON patients and families. The prevalence of LHON in the Dutch population was determined. DESIGN: Observational, retrospective population cohort study. METHODS: The clinical characteristics of LHON patients of 25 families, previously described in 1963, were reevaluated. The mutation and haplotype were determined in the DNA of one affected LHON patient per family. The genotype of their relatives could be deducted, enabling us to evaluate retrospectively the genotype-phenotype correlation. The prevalence of LHON was determined on the basis of anamnestic evaluation of patients in 1963 and by using population registers of that period. RESULTS: The LHON mutation does not influence disease penetrance (50% in male subjects; 10% to 20% in female subjects). More than half of the patients with the 14484 mutation exhibit a partial recovery of vision, regardless of the acuteness of disease onset (P = .001), whereas only 22% of the 11778 carriers and 15.4% of the 3460 carriers recovered. The recovery did not take place within the first year after onset and was uncommon after four years. The onset of LHON is in general very acute but might be more gradual in 11778 carriers and in children. The calculated prevalence of LHON in the Dutch population (1/39,000) is very likely an underestimation caused by a selection bias of familial cases in the original study. CONCLUSIONS: The LHON genotype influences the recovery of vision and disease onset but is unrelated to age, acuteness of onset, or gender. The genotype does not influence disease penetrance. Children might exhibit a slower onset of disease.

Adolescent↗

PubMed2004

Does autosomal dominant pseudoxanthoma elasticum exist?

UNLABELLED: Pseudoxanthoma elasticum (PXE) is a progressive disorder of elastic fibers in skin, eyes, and arterial walls. It is caused by mutations in the ABCC6 gene. Most patients are sporadic cases. The majority of familial cases show autosomal recessive (AR) inheritance, but autosomal dominant (AD) inheritance has also been reported. We reviewed the literature on AD PXE and we studied in detail, both clinically and by DNA studies, a selection of potentially AD pedigrees from our patient population consisting of 59 probands and their family members. Individuals were considered to have definite PXE if they had two of the following three criteria: characteristic ophthalmologic signs, characteristic dermatologic signs, and a positive skin biopsy. In the literature we found only three families with definite PXE in two successive generations and no families with definite PXE in three or more generations. Our own data set comprised three putative AD families. Extensive DNA studies revealed a mutation in only one ABCC6 allele in the patients of these families. Only one of our families showed definite PXE in two generations. Linkage studies revealed that pseudodominance was unlikely in this family. In the other two families AD PXE could not be confirmed after extensive clinical examinations and application of our criteria, since definite PXE was not present in two or more generations. CONCLUSION: the inheritance pattern in PXE usually is AR. Part of the phenotype in family members of PXE patients might be due to expression in heterozygous carriers of an AR disease. AD inheritance in PXE may exist, but is both after careful literature study and in our patient material much rarer than previously thought.

Adolescent↗

PubMedDate not supplied

Pseudoxanthoma elasticum: a clinical, histopathological, and molecular update.

Pseudoxanthoma elasticum is an autosomally inherited disorder that is associated with the accumulation of mineralized and fragmented elastic fibers in the skin, Bruch's membrane in the retina, and vessel walls. The ophthalmic and dermatologic expression of pseudoxanthoma elasticum and its vascular complications are heterogeneous, with considerable variation in phenotype, progression, and mode of inheritance. Using linkage analysis and mutation detection techniques, mutations in the ABCC6 gene were recently implicated in the etiology of pseudoxanthoma elasticum. ABCC6 encodes the sixth member of the ATP-binding cassette transporter and multidrug resistance protein family (MRP6). In humans, this transmembrane protein is highly expressed in the liver and kidney. Lower expression was found in tissues affected by pseudoxanthoma elasticum, including skin, retina, and vessel walls. So far, the substrates transported by the ABCC6 protein and its physiological role in the etiology of pseudoxanthoma elasticum are not known. A functional transport study of rat MRP6 suggests that small peptides such as the endothelin receptor antagonist BQ123 are transported by MRP6. Similar molecules transported by ABCC6 in humans may be essential for extracellular matrix deposition or turnover of connective tissue at specific sites in the body. One of these sites is Bruch's membrane. This review is an update on etiology of pseudoxanthoma elasticum, including its clinical and genetic features, pathogenesis, and biomolecular basis.

Animals↗