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In a family with high HDL, a genetic mutation was identified. In addition to higher HDL levels, carriers had reduced cholesterol efflux from macrophages, impaired platelet function, and attenuated adrenal steroidogenesis. No significant difference was seen in the carotid artery intima–media thickness. A low plasma level of high-density lipoprotein (HDL) cholesterol is a strong risk factor for cardiovascular disease. 1 This explains the interest in the development of HDL cholesterol–increasing drugs to reduce atherosclerosis. To develop such drugs, in-depth knowledge of human HDL metabolism is necessary. Our understanding of several potential targets for drug development has greatly benefited from the identification of families with specific HDL gene mutations. 2 – 5 A prominent example is the interest in inhibiting the cholesterol ester transfer protein (CETP) in response to the discovery that mutations in the CETP gene cause high HDL cholesterol levels. 6 Scavenger receptor class B . . .

Autosomal recessive gene defects are arguably the most important, but least studied genetic causes of severe cognitive dysfunction. Homozygosity mapping in 78 consanguineous Iranian families with nonsyndromic autosomal recessive mental retardation (NS-ARMR) has enabled us to determine the chromosomal localization of at least 8 novel gene loci for this condition. Our data suggest that in the Iranian population NS-ARMR is very heterogeneous, and they argue against the existence of frequent gene defects that account for more than a few percent of the cases.

Very little is known about the molecular basis of autosomal recessive MR (ARMR) because in developed countries, small family sizes preclude mapping and identification of the relevant gene defects. We therefore chose to investigate genetic causes of ARMR in large consanguineous Iranian families. This study reports on a family with six mentally retarded members. Array-based homozygosity mapping and high-resolution microarray-based comparative genomic hybridization (array CGH) revealed a deletion of approximately 150-200 kb, encompassing the promoter and the first six exons of the MCPH1 gene, one out of four genes that have been previously implicated in ARMR with microcephaly. Reexamination of affected individuals revealed a high proportion of prematurely condensed chromosomes, which is a hallmark of this condition, but in spite of the severity of the mutation, all patients showed only borderline to mild microcephaly. Therefore the phenotypic spectrum of MCPH1 mutations may be wider than previously assumed, with ARMR being the only consistent clinical finding.