Linkage of polymorphic congenital cataract to the gamma-crystallin gene locus on human chromosome 2q33-35

Cataract is one of the major causes of blindness in humans. We describe here an autosomal dominant polymorphic congenital cataract (PCC) which is characterised by wide variations in phenotype of non-nuclear lens opacities, even among affected members of the same family. PCC families included a large, unique pedigree (254 members, 103 affected individuals), and genetic linkage was conducted using a variety of polymorphic markers. Evidence for linkage was found for chromosome 2q33- 35 with PCC mapping near D2S72 and TNP1. A tri-nucleotide microsatellite marker for gamma-crystallin B gene (CRYG1) was found to co-segregate with PCC and yielded a maximum lod score of 10.62 at (theta = 0). A multipoint analysis demonstrated that the most probable location of the PCC gene was within an 8 cM genetic interval containing the gamma-crystallin gene cluster. These data provide strong evidence of the existence of an autosomal dominant mutation for PCC in or near the gamma-crystallin gene cluster. This defect is characterised by complete penetrance but variable expression of the cataract phenotype. Our study also suggests that non-nuclear human cataracts might be caused by some abnormality in gamma-crystallin genes.      

Effects of tumor necrosis factor and lymphotoxin on peripheral lymphoid tissue development

Previously, we have reported that neutralization of surface lymphotoxin (LT-alphabeta) in mice which expressed an LT-beta receptor-Fc fusion protein, driven by the cytomegalovirus promoter, resulted in an array of anatomic abnormalities. We now report that mice which express a tumor necrosis factor (TNF) receptor p60-Fc fusion protein (which neutralizes TNF and soluble LT-alpha3 activity) develop unique lymphoid abnormalities. Our data demonstrate that some aspects of peripheral lymphoid organ development require both surface LT-alphabeta and TNF interacting with their specific receptors. However, these related cytokines are also capable of signaling distinct developmental events. Splenic MAdCAM-1 expression, follicular dendritic cell localization and normal Peyer's patch development all require both surface LT-alphabeta and TNF activity. Marginal zone formation and splenic B cell localization primarily require surface LT-alphabeta-LT-beta receptor interactions. Primary follicle formation was dependent upon TNF receptor(s) engagement. Interestingly spleen, lymph nodes and Peyer's patches from TNF receptor p60-Fc-expressing mice all develop different abnormalities, suggesting distinct pathways of development in these lymphoid organs. Thymus development appears to be independent of these signaling pathways. These results demonstrate that TNF and LT are crucial for normal peripheral, but not central lymphoid organ development.      

A high frequency African coding polymorphism in the N-terminal domain of ICAM-1 predisposing to cerebral malaria in Kenya

The malarial parasite Plasmodium falciparum has acted as a potent selective force on the human genome. The particular virulence of this organism is thought to be due to the adherence of parasitised red blood cells to small vessel endothelium through several receptors, including CD36, thrombospondin and intercellular adhesion molecule 1 (ICAM-1, CD54), and parasite isolates differ in their ability to bind to each. Immunohistochemical studies have implicated ICAM-1 as of potential importance in the pathogenesis of cerebral malaria, leading us to reason that if any single receptor were involved in the development of cerebral malaria, then in view of the high mortality of that complication, natural selection should have produced variants with reduced binding capacity. We therefore sequenced the N-terminal domain of ICAM-1 from a number of Africans and discovered a single mutation present at high frequency. Genotypes at this locus from samples from a case-control study indicated an association of the polymorphism with the severity of clinical malaria such that individuals homozygous for the mutation have increased susceptibility to cerebral malaria with a relative risk of two. These counterintuitive results have implications for the mechanism of malaria pathogenesis, resistance to other infectious agents and transplantation immunology.      

The ultrastructure of human reproduction. 1. The natural history of the female germ cell: origin, migration and differentiation inside the developing ovary

This presentation, on both printed copy and CD-ROM, summarizesa series of original data on the ultrastructure of human reproductionproduced by our research group. In particular, female germ cellbehaviour at the time of migration and colonization of the gonadand germ-somatic cell interactions inside the developing ovaryare reviewed from a morphodynamic point of view. The resultsmostly consist of black-and-white transmission and scanningelectron microscopy (TEM and SEM) images. Artificially colouredSEM pictures, light microscopy images and drawings have alsobeen selected for iconography to render complex microanatomicaldetails and their morphofunctional relationships more comprehensible.In all, 35 images are presented in this article, each relatedto a concise text section and accompanied by a self-explainingcaption. A list of pertinent references is also provided.     

ABO blood groups and renal disease

This study compares the frequency of ABO blood group distribution between 184 patients with renal parenchymal diseases and 3,820 apparently healthy subjects. The renal diseases were confirmed by renal biopsy studies in all patients. The distribution of renal patients among the blood groups was significantly different (p less than 0.01) from the blood group distribution of normal subjects. The differences occurred mainly in the B and O Groups with renal patients showing a 7 percent increase in Group B and a 10 percent decrease in Group O.     

Recent decline in age at menarche: The Fels Longitudinal Study

A number of recent reports suggest that the average age at menarche of US girls has declined over the past 20 years. Because the putative declines in the age at menarche are concurrent with increases in childhood body mass index (BMI), it has been suggested that these two trends may be causally linked. We examined differences in mean age of menarche in Fels Longitudinal Study girls who were born in six 10‐year birth cohorts (1930s, 1940s, 1950s, 1960s, 1970s, and 1980s) and simultaneous cohort changes in mean BMI measured cross‐sectionally at selected ages from 3–35 years (n = 371). Girls born in the 1980s had a mean age at menarche of 12.34 years, which was ～3–6 months earlier than that of girls born previously (P < 0.001). While the mean BMI values at ages 25 and 35 generally increased from the 1930s to the 1970s, the mean BMI during childhood and adolescence remained constant across the six birth cohorts. In summary, we found no evidence that the recent decline in the age at menarche in the Fels Longitudinal Study girls was reflected in concurrent increases in BMI at any point in childhood or adolescence. Conversely, girls born in the 1960s and 1970s have subsequently become heavier in young and mid‐adulthood than were girls from earlier birth cohorts, without any concurrent change in the mean age at menarche over that time period. These two findings suggest that population‐level shifts in BMI and the timing of menarche are largely independent, although sometimes coincident, processes. Am. J. Hum. Biol. 16:453–457, 2004. © 2004 Wiley‐Liss, Inc.     

The oral-facial-digital syndrome type 1 (OFD1), a cause of polycystic kidney disease and associated malformations, maps to Xp22.2-Xp22.3

Key features of the oral-facial-digital syndrome type 1 (OFD1) include malformations of the face, oral cavity and digits. In addition, the clinical phenotype often includes mental retardation and renal functional impairment. Approximately 75% of cases of OFD1 are sporadic, and the condition occurs almost exclusively in females. In familial cases, the most likely mode of inheritance is considered to be X-linked dominant with prenatal lethality in affected males. Therefore, the OFD1 gene product appears to have widespread importance in organogenesis and is essential for fetal survival. We have studied two kindreds in which the clinical course was dominated by polycystic kidney disease requiring dialysis and transplantation. Using polymorphic chromosome markers spaced at approximately 10 cM intervals along the X chromosome, we mapped the disease to a region on the short arm of the X chromosome (Xp22.2-Xp22.3) spanning 19.8 cM and flanked by crossovers with the markers DXS996 and DX7S105. There was a maximum lod score of 3.32 in an 'affecteds only' analysis using a marker within the KAL gene (theta = 0.0 ), thereby confirming the location of the gene for OFD1 on the X chromosome. The remainder of the X chromosome was excluded by recombinants in affected individuals. The importance of our findings includes the definitive assignment of this male-lethal disease to the X chromosome and the mapping of a further locus for a human polycystic kidney disease. Furthermore, this mapping study suggests a possible mouse model for OFD1 as the X-linked dominant Xpl mutant, in which polydactyly and renal cystic disease occurs, maps to the homologous region of the mouse X chromosome.