Charcot-Marie-Tooth phenotype produced by a duplicated PMP22 gene as part of a 17P trisomy-translocation to the X chromosome

The Charcot-Mane-Tooth disease type 1A (CMTlA) phenotype is most often associated with a 1.5 megabase (mb), tandem duplication of chromosome 17 band p12 (17˜12). The prevailing hypothesis is that the demyelinating neuropathy results from a dosage effect of the peripheral myelin protein gene PMP22 which is included within this duplication. We present a patient with clinical and electrophysiological features ofCMTlA in whom an extra PMP22 gene resulted from a rare unbalanced translocation of 17p to the X chromosome. This finding further supports the hypothesis of gene dosage as the basis for CMTlA. More-over, this case highlights the importance of fluorescence in siiu hybridization (FISH) as an alternative molecular technique in the diagnosis of CMTlA.     

Inhibition of the Mixed Lymphocyte Culture Response by Antibody Following Successful Human Renal Transplantation

Immunoglobulin G, appearing after several months in the serum of a recipient of a successful kidney transplant from a closely matched sibling donor, was demonstrated to progressively inhibit unidirectional mixed lymphocyte cultures when donor lymphocytes were used either in responding or stimulating cell populations. The active recipient IgG had no effect in cultures in which donor cells were not used, nor did IgG obtained from other individuals show nonspecific inhibitory effects on cultures containing donor cells. It is suggested that the MLC inhibitory immunoglobulin may serve an immunoregulatory function after renal transplantation.     

Life expectancy in British Marfan syndrome populations

A total of 206 patients with Marfan syndrome were ascertained throughout genetic clinics in Wales and Scotland during the period 1970–1990. There were 45 deaths representing 22% of the cohort. Mean age at death was 45.3 ± 16.5 years. 50% median cumulative survival in the total cohort (n = 206) was 53 years for males and 72 years for females. Multivariate analysis confirmed severity as the best independent indicator of survival. These findings and survival curves will assist in the counselling of British families and individuals with Marfan syndrome.     

The GAP-related domain of tuberin, the product of the TSC2 gene, is a target for missense mutations in tuberous sclerosis

Tuberous sclerosis is an autosomal dominant trait in which the dysregulation of cellular proliferation and differentiation results in the development of hamartomatous growths in many organs. The TSC2 gene is one of two genes determining tuberous sclerosis. Inactivating germline mutations of TSC2 in patients with tuberous sclerosis and somatic loss of heterozygosity at the TSC2 locus in the associated hamartomas indicate that TSC2 functions as a tumour suppressor gene and that loss of function is critical to expression of the tuberous sclerosis phenotype. The TSC2 product, tuberin, has a region of homology with the GTPase activating protein rap1GAP and stimulates the GTPase activity of rap1a and rab5a in vitro. Here we show that the region of homology between tuberin and human rap1GAP and the murine GAP mSpa1 is more extensive than previously reported and spans approximately 160 amino acid residues encoded within exons 34-38 of the TSC2 gene. Single strand conformation polymorphism analysis of these exons in 173 unrelated patients with tuberous sclerosis and direct sequencing of variant conformers together with study of additional family members enabled characterisation of disease associated mutations in 14 cases. Missense mutations, which occurred in exons 36, 37 and 38 were identified in eight cases, four of whom shared the same recurrent change P1675L. Each of the five different missense mutations identified was shown to occur de novo in at least one sporadic case of tuberous sclerosis. The high proportion of missense mutations detected in the region of the TSC2 gene encoding the GAP-related domain supports its key role in the regulation of cellular growth.      

Isolation and characterization of human and rabbit sperm tail fibrous sheath

Using mechanical and chemical dissection methods, fibrous sheath was isolated both from normal ejaculated human spermatozoa and from rabbit cauda epididymal spermatozoa. The same techniques did not produce a pure preparation of fibrous sheath from ejaculated rabbit spermatozoa, suggesting that further cross-linking and stabilization of sperm structures occurs in response to components of the seminal plasma. The isolation procedures were monitored by phase contrast microscopy and the purity of the fibrous sheath was verified by electron microscopy. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) of isolated human fibrous sheath revealed at least 14 protein bands of which the most intensely stained were of molecular weight 84, 72, 66.2, 57, 32 and 28.5 kDa. The rabbit fibrous sheath revealed at least 10 protein bands, of which the most intensely stained were 35.2, 32.7 and 28.5 kDa. The amino acid composition of the purified fibrous sheath from human and rabbit spermatozoa was similar, being high in aspartic acid and/or asparagine and glutamic acid and/or glutamine, serine, alanine, leucine, lysine and glycine, but low in histidine, tyrosine and isoleucine. This composition is similar to that reported for the rat and suggests that mammalian sperm tail fibrous sheaths are composed of similar types of proteins, although there are apparent differences in protein components between species.