Increased SERCA2a sub-cellular heterogeneity in right-ventricular heart failure inhibits excitation-contraction coupling and modulates arrhythmogenic dynamics.

The intracellular calcium handling system of cardiomyocytes is responsible for controlling excitation-contraction coupling (ECC) and has been linked to pro-arrhythmogenic cellular phenomena in conditions such as heart failure (HF). SERCA2a, responsible for intracellular uptake, is a primary regulator of calcium homeostasis, and remodelling of its function has been proposed as a causal factor underlying cellular and tissue dysfunction in disease. Whereas adaptations to the global (i.e. whole-cell) expression of SERCA2a have been previously investigated in the context of multiple diseases, the role of its spatial profile in the sub-cellular volume has yet to be elucidated. We present an approach to characterize the sub-cellular heterogeneity of SERCA2a and apply this approach to quantify adaptations to the length-scale of heterogeneity (the distance over which expression is correlated) associated with right-ventricular (RV)-HF. These characterizations informed simulations to predict the functional implications of this heterogeneity, and its remodelling in disease, on ECC, the dynamics of calcium-transient alternans and the emergence of spontaneous triggered activity. Image analysis reveals that RV-HF is associated with an increase in length-scale and its inter-cellular variability; simulations predict that this increase in length-scale can reduce ECC and critically modulate the vulnerability to both alternans and triggered activity. This article is part of the theme issue 'The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease'.

Exclusion of two candidate pigment loci, c and b, part of chromosome 11p, and 33 random polymorphic markers as the locus for tyrosinase-positive oculocutaneous albinism.

The locus for Tyrosinase-Positive Oculocutaneous Albinism (ty-pos OCA) has not yet been localised. The search for the ty-pos OCA locus has included a search for linkage to candidate pigment loci and a candidate chromosomal region, as well as a random search using highly polymorphic markers in 42 families, including 271 individuals of whom 79 are affected. The lod scores for the tyrosinase (TYR) locus (11q14-q21), homologous to the albino locus, c, in the mouse and the CAS2/TRP1 locus (9p22-pter), homologous to the brown locus, b, in the mouse were -5.89 and -7.22, respectively, at a recombination fraction of theta = 0.01, thus excluding them from being the ty-pos OCA locus. In the candidate chromosomal region, 11p, four loci (probes) were tested, SAA (pSAA82), CALC (pHC36), HBB (Gamma-globin haplotype) and an AC repeat polymorphism at the Wilm's Tumour locus (WT1). A portion of 11p was excluded with the following lod scores: pSAA82 lod = -2.05 at theta = 0.10; pHC36 lod = -3.87 at theta = 0.05; gamma-globin haplotype lod = -2.80 at theta = 0.10; and WT1 lod = -2.34 at theta = 0.10. Thirty-three polymorphic markers randomly distributed on 13 different chromosomes were all excluded from close linkage to ty-pos OCA.

The tyrosinase-positive oculocutaneous albinism locus maps to chromosome 15q11.2-q12.

Tyrosinase-positive oculocutaneous albinism (ty-pos OCA), an autosomal recessive disorder of the melanin biosynthetic pathway, is the most common type of albinism occurring worldwide. In southern African Bantu-speaking negroids it has an overall prevalence of about 1/3,900. Since the basic biochemical defect is unknown, a linkage study with candidate loci, candidate chromosomal regions, and random loci was undertaken. The ty-pos OCA locus was found to be linked to two arbitrary loci, D15S10 and D15S13, in the Prader-Willi/Angelman chromosomal region on chromosome 15q11.2-q12. The pink-eyed dilute locus, p, on mouse chromosome 7, maps close to a region of homology on human chromosome 15q, and we postulate that the ty-pos OCA and p loci are homologous.

Mapping the human CAS2 gene, the homologue of the mouse brown (b) locus, to human chromosome 9p22-pter.

Melanin biosynthesis is a multistep process with the first step being the conversion of L-tyrosine to L-Dopa catalyzed by the enzyme tyrosinase. The enzymes which catalyze the other steps of melanogenesis are not known. One murine pigmentation gene, the brown (b) locus, when mutated, leads to a brown or hypopigmented coat. The b-locus protein has been shown to display catalase activity. The human b-locus, therefore, is designated as CAS2. We used the mouse b-locus cDNA to isolate the human homologue, which in turn, was used to map the CAS2 locus to a human chromosome. The potential CAS2 protein codes for 527 amino acids containing a putative signal sequence and transmembrane domain. The CAS2 protein has primary and probably secondary structures similar to human tyrosinase. The CAS2 was mapped to human Chromosome 9 by somatic cell hybridization and, more specifically, to 9p22-pter by in situ hybridization. The assignment of CAS2 on the human Chromosome 9 extends this region of known homology on mouse Chromosome 4.

In quest of the tyrosinase-positive oculocutaneous albinism gene.

The gene which causes tyrosinase-positive oculocutaneous albinism (ty-pos OCA) is not known. Forty-seven Bantu-speaking Negroid families with ty-pos OCA were studied in an attempt to find linkage to the gene. Fifteen 'classical' and seven DNA polymorphisms were used in the search for linkage. Close linkage was excluded for the Rh, Gc and beta-globin loci. There is no suggestion of linkage to MNS, ABO, PGM1, 6PGD, ACP1, GPX1, GLO1, GPT1, PEP A, Tf, alpha 1-AT, Hp, DQA, DXA and three arbitrary restriction fragment length polymorphisms (RFLPs). There is a slightly positive lod score for pAW101 (D14S1) (0.591 for theta = 0.2). An 'interesting' lod score was obtained with Bf and a haplotype generated by the markers DQA and DXA (1.575 for theta = 0.1 and 0.979 for theta = 0.2, respectively). Further testing of markers on chromosome 6p are indicated. Although ty-pos OCA in Southern Africa is likely to be a homogeneous disorder, genetic heterogeneity cannot be excluded as differences due to the presence/absence of ephelides within families have been observed. To date 57% of the genome has been excluded from linkage with ty-pos OCA.