Neurodegenerative disorders such as Parkinson and Alzheimer disease cause motor and cognitive dysfunction and belong to a heterogeneous group of common and disabling disorders. Although the complex molecular pathophysiology of neurodegeneration is largely unknown, major advances have been achieved by elucidating the genetic defects underlying mendelian forms of these diseases. This has led to the discovery of common pathophysiological pathways such as enhanced oxidative stress, protein misfolding and aggregation and dysfunction of the ubiquitin-proteasome system. Here, we describe loss-of-function mutations in a previously uncharacterized, predominantly neuronal P-type ATPase gene, ATP13A2, underlying an autosomal recessive form of early-onset parkinsonism with pyramidal degeneration and dementia (PARK9, Kufor-Rakeb syndrome). Whereas the wild-type protein was located in the lysosome of transiently transfected cells, the unstable truncated mutants were retained in the endoplasmic reticulum and degraded by the proteasome. Our findings link a class of proteins with unknown function and substrate specificity to the protein networks implicated in neurodegeneration and parkinsonism.

Neurodegenerative disorders with high brain iron include Parkinson disease, Alzheimer disease and several childhood genetic disorders categorized as neuroaxonal dystrophies. We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome. This discovery implicates phospholipases in the pathogenesis of neurodegenerative disorders with iron dyshomeostasis.

Mutations in the ASPM gene at the MCPH5 locus are expected to be the most common cause of human autosomal recessive primary microcephaly (MCPH), a condition in which there is a failure of normal fetal brain development, resulting in congenital microcephaly and mental retardation. We have performed the first comprehensive mutation screen of the 10.4-kb ASPM gene, identifying all 19 mutations in a cohort of 23 consanguineous families. Mutations occurred throughout the ASPM gene and were all predicted to be protein truncating. Phenotypic variation in the 51 affected individuals occurred in the degree of microcephaly (5-11 SDs below normal) and of mental retardation (mild to severe) but appeared independent of mutation position.

No abstract

C olorectal cancer (CRC) is the third most common cancer diagnosed in both men and women, and the second most common cause of cancer deaths in the United States. There were approximately 150 000 new cases resulting in 57 000 deaths in 2002.1 CRC is one of the most studied cancer types and its underlying aetiology best elucidated. Colorectal tumorigenesis involves a multistep process including genetic and epigenetic alterations of numerous CRC related genes that may act as either oncogenes or tumour suppressor genes. [2][3][4][5] The majority of sporadic CRCs are characterised by deletions of large chromosomal segments, which are thought to represent the loss of wild type tumour suppressor genes.6 7 About 15% of sporadic CRCs, on the other hand, show microsatellite instability (MSI), characterised by the insertion and/or deletion of simple repeat sequences and indicative of the involvement of defective mismatch repair. Birt-Hogg-Dubé syndrome (BHD, OMIM 135150) is an inherited autosomal dominant syndrome characterised by a triad of cutaneous lesions consisting of fibrofolliculomas, trichodiscomas, and acrochordons. 10 A wide spectrum of neoplastic and non-neoplastic features has been described in BHD patients, 11 including diverse types of kidney tumours 12-17 and spontaneous pneumothorax.12-16 18 BHD has also been reported to be associated with colonic polyposis and colorectal neoplasia, 13 19-22 although a large study of 223 patients from 33 BHD families could not establish such a relation. 23 We recently reported a high incidence of colorectal polyps and carcinomas in patients with confirmed BHD germline mutations, indicating that the BHD gene may be involved in colorectal tumorigenesis. 13 The BHD gene has been mapped to chromosome subband 17p11.2 12 14 and recently identified to encode a novel protein named follicullin. 15 Based on the presence of inactivating BHD mutations in BHD patients, and the detection of LOH in a significant proportion of BHD related tumours, the BHD gene was considered to be a tumour suppressor gene. A 44% frequency of frameshift mutations within a mononucleotide (C) 8 tract (nt 1733-1740) has been detected in BHD patients, 15 and this repeat tract represents a BHD mutational hot spot.13 15 Other studies have reported the presence of frameshift mutations within intragenic mononucleotide tracts of the TGFBR2 and BAX genes in CRC cell lines and tumours with high level MSI.24 25 The poly C tract of the BHD gene may therefore be a potential site of mutation in CRC characterised by MSI.We have evaluated the role of the BHD gene in 47 unselected colorectal tumours (10 polyps and 37 carcinomas) by screening all coding exons of the BHD gene for mutations and analysing 46 of the tumours for LOH in the chromosome region surrounding the BHD locus. Furthermore, alterations in BHD promoter methylation profiles were determined in 23 cases of matched normal/carcinoma tissues where a sufficient quantity of DNA was available. We report the detection of two novel somatic missense mutations of ...