Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease.

A shared genetic susceptibility between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) has been suggested. We investigated this by assessing the contribution of rare variants in genes involved in CMM to PD risk. We studied rare variation across 29 CMM risk genes using high-quality genotype data in 6875 PD cases and 6065 controls and sought to replicate findings using whole-exome sequencing data from a second independent cohort totaling 1255 PD cases and 473 controls. No statistically significant enrichment of rare variants across all genes, per gene, or for any individual variant was detected in either cohort. There were nonsignificant trends toward different carrier frequencies between PD cases and controls, under different inheritance models, in the following CMM risk genes: BAP1, DCC, ERBB4, KIT, MAPK2, MITF, PTEN, and TP53. The very rare TYR p.V275F variant, which is a pathogenic allele for recessive albinism, was more common in PD cases than controls in 3 independent cohorts. Tyrosinase, encoded by TYR, is the rate-limiting enzyme for the production of neuromelanin, and has a role in the production of dopamine. These results suggest a possible role for another gene in the dopamine-biosynthetic pathway in susceptibility to neurodegenerative Parkinsonism, but further studies in larger PD cohorts are needed to accurately determine the role of these genes/variants in disease pathogenesis.

The rs5743836 polymorphism in TLR9 confers a population-based increased risk of non-Hodgkin lymphoma.

Non-Hodgkin lymphoma (NHL) has been associated with immunological defects, chronic inflammatory and autoimmune conditions. Given the link between immune dysfunction and NHL, genetic variants in toll-like receptors (TLRs) have been regarded as potential predictive factors of susceptibility to NHL. Adequate anti-tumoral responses are known to depend on TLR9 function, such that the use of its synthetic ligand is being targeted as a therapeutic strategy. We investigated the association between the functional rs5743836 polymorphism in the TLR9 promoter and risk for B-cell NHL and its major subtypes in three independent case-control association studies from Portugal (1160 controls, 797 patients), Italy (468 controls, 494 patients) and the US (972 controls, 868 patients). We found that the rs5743836 polymorphism was significantly overtransmitted in both Portuguese (odds ratio (OR), 1.85; P=7.3E-9) and Italian (OR, 1.84; P=6.0E-5) and not in the US cohort of NHL patients. Moreover, the increased transcriptional activity of TLR9 in mononuclear cells from patients harboring rs5743836 further supports a functional effect of this polymorphism on NHL susceptibility in a population-dependent manner.

Loss of function of DJ-1 triggered by Parkinson's disease-associated mutation is due to proteolytic resistance to caspase-6.

DJ-1 was recently identified as a gene product responsible for a subset of familial Parkinson's disease (PD). The mechanisms by which mutations in DJ-1 alter its function and account for PD-related pathology remained largely unknown. We show that DJ-1 is processed by caspase-6 and that the caspase-6-derived C-terminal fragment of DJ-1 fully accounts for associated p53-dependent cell death. In line with the above data, we show that a recently described early-onset PD-associated mutation (D149A) renders DJ-1 resistant to caspase-6 proteolysis and abolishes its protective phenotype. Unlike the D149A mutation, the L166P mutation that prevents DJ-1 dimerization does not impair its proteolysis by caspase-6 although it also abolishes DJ-1 antiapoptotic function. Therefore, we show here that DJ-1 loss of function could be due to impaired caspase-6 proteolysis and we document the fact that various DJ-1 mutations could lead to PD pathology through distinct molecular mechanisms.

PINK-1 and DJ-1--new genes for autosomal recessive Parkinson's disease.

Our genetic knowledge of Parkinson's disease (PD) is moving forward at an impressive speed. In less then 10 years family-based linkage analysis and positional cloning have led to the identification of several genes for familial forms of PD, which has been of critical importance to the scientific advance of PD research as the causal genes have offered new tools to model and understand pathways leading to neurodegeneration in PD.

A novel susceptibility locus for Hirschsprung's disease maps to 4q31.3-q32.3.

We report on a multigenerational family with isolated Hirschsprung's disease (HSCR). Five patients were affected by either short segment or long segment HSCR. The family consists of two main branches: one with four patients (three siblings and one maternal uncle) and one with one patient. Analysis of the RET gene, the major gene involved in HSCR susceptibility, revealed neither linkage nor mutations. A genome wide linkage analysis was performed, revealing suggestive linkage to a region on 4q31-q32 with a maximum parametric multipoint LOD score of 2.7. Furthermore, non-parametric linkage (NPL) analysis of the genome wide scan data revealed a NPL score of 2.54 (p = 0.003) for the same region on chromosome 4q (D4S413-D4S3351). The minimum linkage interval spans a region of 11.7 cM (12.2 Mb). No genes within this chromosomal interval have previously been implicated in HSCR. Considering the low penetrance of disease in this family, the 4q locus may be necessary but not sufficient to cause HSCR in the absence of modifying loci elsewhere in the genome. Our results suggest the existence of a new susceptibility locus for HSCR at 4q31.3-q32.3.

Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly.

BACKGROUND: Porencephaly (cystic cavities of the brain) is caused by perinatal vascular accidents from various causes. Several familial cases have been described and autosomal dominant inheritance linked to chromosome 13q has been suggested. COL4A1 is an essential component in basal membrane stability. Mouse mutants bearing an in-frame deletion of exon 40 of Col4a1 either die from haemorrhage in the perinatal period or have porencephaly in survivors. A report of inherited mutations in COL4A1 in two families has shown that familial porencephaly may have the same cause in humans. OBJECTIVE: To describe three novel COL4A1 mutations. RESULTS: The three mutations occurred in three unrelated Dutch families. There were two missense mutations of glycine residues predicted to result in abnormal collagen IV assembly, and one mutation predicted to abolish the traditional COL4A1 start codon. The last mutation was also present in an asymptomatic obligate carrier with white matter abnormalities on brain magnetic resonance imaging. CONCLUSIONS: This observation confirms COL4A1 as a major locus for genetic predisposition to perinatal cerebral haemorrhage and porencephaly and suggests variable expression of COL4A1 mutations.

Brachydactyly and short stature in a kindred with early-onset parkinsonism.

In a Dutch kindred we have identified a deletion of the DJ-1 gene, leading to autosomal-recessive parkinsonism. The parkinsonism patients also had short stature and brachydactyly. In the family and a control group from the same community, we used the DJ-1 deletion as a marker for the originally linked PARK7 region and found a significant association with body height (P = 0.005), which suggests a gene in linkage disequilibrium with DJ-1 to be implicated in short stature. Analysis of hand-bone length showed incomplete segregation of the PARK7 region with brachydactyly, such that a gene in PARK7 is unlikely to fully explain the brachydactyly. Since the bone length reduction was more pronounced in the homozygous parkinsonism patients than in their heterozygous relatives, however, the PARK7 region may contain a modifier gene for growth.

Unraveling the pathogenesis of Parkinson's disease--the contribution of monogenic forms.

The field of Parkinson's disease pathogenesis is rapidly evolving from the one of a monolithic and obscure entity into the one of a complex scenario with several known molecular players. The ongoing systematic exploration of the genome holds great promise for the identification of the genetic factors conferring susceptibility to the common non-Mendelian forms of this disease. However, most of the progress of the last 5 years has come from the successful mapping and cloning of genes responsible for rare Mendelian variants of Parkinson's disease. These discoveries are providing tremendous help in understanding the molecular mechanisms of this devastating disease. Here we review the genetics of the monogenic forms of Parkinson's disease. Moreover, we focus on the mechanisms of disease caused by alpha-synuclein and parkin mutations, and the implications of this growing body of knowledge for understanding the pathogenesis of the common forms of the disease.

Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly.

A large three-generation family with autosomal dominant type 1 porencephaly from southern Italy was studied. A high rate of miscarriages was observed. Of the nine affected individuals, four displayed a severe phenotype, and five had slight pyramidal signs or mild cognitive abnormalities. The MRI study disclosed unilateral porencephalic cyst, or colpocephaly. A genome-wide screen resulted in suggestive evidence for linkage to chromosome 13qter with a maximum logarithm-of-the-odds score of 3.16, from multipoint analysis, with marker D13S285.

DJ-1 (PARK7) mutations are less frequent than Parkin (PARK2) mutations in early-onset Parkinson disease.

BACKGROUND: Mutations in the Parkin gene (PARK2) are the most commonly identified cause of recessively inherited early-onset Parkinson disease (EOPD) but account for only a portion of cases. DJ-1 (PARK7) was recently reported as a second gene associated with recessively inherited PD with a homozygous exon deletion and a homozygous point mutation in two families. METHODS: To investigate the frequency of DJ-1 mutations, the authors performed mutational analysis of all six coding exons of DJ-1 in 100 EOPD patients. For the detection of exon rearrangements, the authors developed a quantitative duplex PCR assay. Denaturing high performance liquid chromatography analysis was used to screen for point mutations and small deletions. Further, Parkin analysis was performed as previously described. RESULTS: The authors identified two carriers of single heterozygous loss-of-function DJ-1 mutations, including a heterozygous deletion of exons 5 to 7 and an 11-base pair deletion, removing the invariant donor splice site in intron 5. Interestingly, both DJ-1 mutations identified in this study were found in the heterozygous state only. The authors also detected a polymorphism (R98Q) in 1.5% of the chromosomes in both the patient and control group. In the same patient sample, 17 cases were detected with mutations in the Parkin gene. CONCLUSIONS: Mutations in DJ-1 are less frequent than mutations in Parkin in EOPD patients but should be considered as a possible cause of EOPD. The effect of single heterozygous mutations in DJ-1 on the nigrostriatal system, as described for heterozygous changes in Parkin and PARK6, remains to be elucidated.

Screening for DJ-1 mutations in early onset autosomal recessive parkinsonism.

The DJ-1 gene was identified as responsible for early onset autosomal recessive parkinsonism in two families (PARK7). In this study, after excluding mutations in the parkin gene, the authors screened a large series of early onset autosomal recessive parkinsonism families and consanguineous isolated patients of diverse geographic origins for DJ-1 mutations. No mutations were found. This indicates that PARK7 is not a common locus for early onset autosomal recessive parkinsonism, and that one or more new loci remains to be identified.

DJ-1( PARK7), a novel gene for autosomal recessive, early onset parkinsonism.

Four chromosomal loci ( PARK2, PARK6, PARK7, and PARK9) associated with autosomal recessive, early onset parkinsonism are known. We mapped the PARK7 locus to chromosome 1p36 in a large family from a genetically isolated population in the Netherlands, and confirmed this linkage in an Italian family. By positional cloning within the refined PARK7 critical region we recently identified mutations in the DJ-1 gene in the two PARK7-linked families. The function of DJ-1 remains largely unknown, but evidence from genetic studies on the yeast DJ-1 homologue, and biochemical studies in murine and human cell lines, suggests a role for DJ-1 as an antioxidant and/or a molecular chaperone. Elucidating the role of DJ-1 will lead to a better understanding of the pathogenesis of DJ-1-related and common forms of Parkinson's disease.

Familial multiple epiphyseal dysplasia due to a matrilin-3 mutation: further delineation of the phenotype including 40 years follow-up.

In this study, we followed-up the family with bilateral hereditary micro-epiphyseal dysplasia (BHMED) originally described by Elsbach [1959: J Bone Joint Surg [Br] 41-B:514-523]. Clinical re-examination of all available family members resulted in further delineation of the clinical and radiological phenotype, which is distinct from common multiple epiphyseal dysplasia (MED). Linkage analysis excluded EDM1, EDM2, and EDM3 as candidate genes. Linkage and mutation analysis of matrilin-3 (MATN-3) revealed a new pathogenic mutation confirming that BHMED is indeed a distinct disease entity among MED and MED-like disorders.

[Radiologische Besonderheiten einer bilateral vererblichen Mikro-Epiphysendysplasie - deutliche Entität einer Skelettdysplasie]. / Radiological features of bilateral hereditary micro-epiphyseal dysplasia--a distinct entity in the skeletal dysplasias.

AIM: To prove that bilateral hereditary micro-epiphyseal dysplasia (BHMED), first described by Elsbach in 1959, is a distinct disorder radiologically as well as clinically, compared with multiple epiphyseal dysplasia (MED). MATERIAL AND METHODS: We used the data of the revised pedigree with 84 family members, performed a medical history, physical examination and made a radiological evaluation for defining a clinical and radiological phenotype of BHMED family members. We used blood samples for genetic analysis. RESULTS: Although there is a clear clinical picture of the dysplasia, the radiological signs are more reliable for making the diagnosis. Especially the typical deformity of the hip and knee joint are diagnostic for BHMED. By linkage analysis we excluded linkage with the three known MED-loci (EDM1, EDM2 and EDM3). CONCLUSION: BHMED is indeed an entity that is distinct from common multiple epiphyseal dysplasia (MED), clinically, as well as radiologically and genetically.

Bilateral hereditary micro-epiphyseal dysplasia: further delineation of the phenotype with 40 years follow-up.

Bilateral hereditary micro-epiphyseal dysplasia (BHMED) is a distinct skeletal dysplasia with specific clinical and radiological findings. It was first published in 1959. We have re-examined the original family for further delineation of the phenotype.

Mutation-dependent aggregation of tau protein and its selective depletion from the soluble fraction in brain of P301L FTDP-17 patients.

Mutations in the gene for the microtubule-associated protein tau are associated with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). In this study we compared the presence of the P301L mutated tau protein from brain material of patients with that of the normal 4-repeat, using polyclonal antibodies specific for the P301L point mutation and its normal counterpart. We determined the relative ratio of mutated versus normal tau protein in the sarkosyl-soluble and -insoluble protein fractions from several brain regions. Although mutated and normal tau proteins are both present in the sarkosyl-insoluble deposits, quantitative analysis showed that the mutated protein is the major component. In the sarkosyl-soluble fraction of frontal and temporal cortex the overall ratio of 3-repeat versus 4-repeat tau isoforms is unchanged but there is a dramatic depletion of mutant tau protein. Furthermore, we observed an increase in tau-immunoreactive cleavage products with the P301L antibody, suggesting that the mutant protein is partly resistant to degradation and this is confirmed by pulse-chase experiments. This is the first direct evidence using patient material that shows a selective aggregation of mutant tau protein resulting in sarkosyl-insoluble deposits and the specific depletion of mutated tau protein in the soluble fraction.

Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome.

Greig cephalopolysyndactyly syndrome, characterized by craniofacial and limb anomalies (GCPS; MIM 175700), previously has been demonstrated to be associated with translocations as well as point mutations affecting one allele of the zinc finger gene GLI3. In addition to GCPS, Pallister-Hall syndrome (PHS; MIM 146510) and post-axial polydactyly type A (PAP-A; MIM 174200), two other disorders of human development, are caused by GLI3 mutations. In order to gain more insight into the mutational spectrum associated with a single phenotype, we report here the extension of the GLI3 mutation analysis to 24 new GCPS cases. We report the identification of 15 novel mutations present in one of the patient's GLI3 alleles. The mutations map throughout the coding gene regions. The majority are truncating mutations (nine of 15) that engender prematurely terminated protein products mostly but not exclusively N-terminally to or within the central region encoding the DNA-binding domain. Two missense and two splicing mutations mapping within the zinc finger motifs presumably also interfere with DNA binding. The five mutations identified within the protein regions C-terminal to the zinc fingers putatively affect additional functional properties of GLI3. In cell transfection experiments using fusions of the DNA-binding domain of yeast GAL4 to different segments of GLI3, transactivating capacity was assigned to two adjacent independent domains (TA(1)and TA(2)) in the C-terminal third of GLI3. Since these are the only functional domains affected by three C-terminally truncating mutations, we postulate that GCPS may be due either to haploinsufficiency resulting from the complete loss of one gene copy or to functional haploinsufficiency related to compromised properties of this transcription factor such as DNA binding and transactivation.

Clinical and genetic studies on 12 preaxial polydactyly families and refinement of the localisation of the gene responsible to a 1.9 cM region on chromosome 7q36.

Polydactyly is the most frequently observed congenital hand malformation with a prevalence between 5 and 19 per 10000 live births. It can occur as an isolated disorder, in association with other hand/foot malformations, or as a part of a syndrome, and is usually inherited as an autosomal dominant trait. According to its anatomical location, polydactyly can be generally subdivided into pre- and postaxial forms. Recently, a gene responsible for preaxial polydactyly types II and III, as well as complex polysyndactyly, has been localised to chromosome 7q36. In order to facilitate the search for the underlying genetic defect, we ascertained 12 additional families of different ethnic origin affected with preaxial polydactyly. Eleven of the kindreds investigated could be linked to chromosome 7q36, enabling us to refine the critical region for the preaxial polydactyly gene to a region of 1.9 cM. Our findings also indicate that radial and tibial dysplasia/aplasia can be associated with preaxial polydactyly on chromosome 7q36. Combining our results with other studies suggests that all non-syndromic preaxial polydactylies associated with triphalangism of the thumb are caused by a single genetic locus, but that there is genetic heterogeneity for preaxial polydactyly associated with duplications of biphalangeal thumbs. Comparison of the phenotypic and genetic findings of different forms of preaxial polydactyly is an important step in analysing and understanding the aetiology and pathogenesis of these limb malformations.

Genetics of limb development and congenital hand malformations.

The vertebrate limb bud develops along three different axes: proximodistal, anteroposterior, and dorsoventral. Several genetic factors responsible for control of each of the three limb axes have been identified. The genes involved interact in complex feedback loops to achieve proper arrangement and differentiation of tissues. Most of the available information on limb development and patterning has come from studies carried out in the lower vertebrates. In recent years, an increasing number of studies have been unraveling the genetic basis of human hand malformation phenotypes. At present, genes responsible for preaxial polydactyly, split hand/split foot malformation, and brachydactyly type C have been localized, and the gene responsible for synpolydactyly has been identified. In this paper, we present an overview of the genetic factors involved in limb development, followed by summarized discoveries in the genetics of human congenital hand malformations.

The genetic background of craniosynostosis syndromes.

Craniosynostosis syndromes are developmental disorders that cause an abnormal shape of the skull due to the premature fusion of cranial sutures. Enormous progress has been made recently in understanding the genetic background of these disorders and a classification of syndromes on a genetic basis is beginning to emerge. Members of at least three gene families that play an important role in vertebrate development are associated with different craniosynostosis syndromes. Here we review the genetic aspects of this fast-moving field.