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PubMed2002

Polydactyly: how many disorders and how many genes?

Disorders that include polydactyly as a manifestation are diverse and numerous. Cataloging these disorders by phenotype and genotype demonstrates numerous overlapping phenotypes, genetic heterogeneity of phenotypes, and distinct phenotypes generated from mutations in single genes. To assess these issues, a list of disorders with polydactyly has been compiled from several sources. Among 119 disorders, 39 disorders are associated with mutations in genes, and among these, genotypic and phenotypic overlap is demonstrated. These issues highlight the need for a diagnostic system that catalogs both genotype and phenotype. Published 2002 Wiley-Liss, Inc.

Abnormalities, Multiple↗
PubMed2003

Identification of genetically linked RGAs by BAC screening in maize and implications for gene cloning, mapping and MAS.

The resistance gene analogue (RGA) pic19 in maize, a candidate for sugarcane mosaic virus (SCMV) resistance gene (R gene) Scmv1, was used to screen a maize BAC library to identify homologous sequences in the maize genome and to investigate their genomic organisation. Fifteen positive BAC clones were identified and could be classified into five physically independent contigs consisting of overlapping clones. Genetic mapping clustered three contigs into the same genomic region as Scmv1 on chromosome 6S. The two remaining contigs mapped to the same region as a QTL for SCMV resistance on chromosome 1. Thus, RGAs mapping to a target region can be successfully used to identify further-linked candidate sequences. The pic19 homologous sequences of these clones revealed a sequence similarity of 94-98% on the nucleotide level. The high sequence similarity reveals potential problems for the use of RGAs as molecular markers. Their application in marker-assisted selection (MAS) and the construction of high-density genetic maps is complicated by the existence of closely linked homologues resulting in 'ghost' marker loci analogous to 'ghost' QTLs. Therefore, implementation of genomic library screening, including genetic mapping of potential homologues, seems necessary for the safe application of RGA markers in MAS and gene isolation.

Base Sequence↗
PubMed2006

Genetics of affective (mood) disorders.

The enormous public health importance of mood disorders, when considered alongside their substantial heritabilities, has stimulated much work, predominantly in bipolar disorder but increasingly in unipolar depression, aimed at identifying susceptibility genes using both positional and functional molecular genetic approaches. Several regions of interest have emerged in linkage studies and, recently, evidence implicating specific genes has been reported; the best supported include BDNF and DAOA but further replications are required and phenotypic relationships and biological mechanisms need investigation. The complexity of psychiatric phenotypes is demonstrated by (a) the evidence accumulating for an overlap in genetic susceptibility across the traditional classification systems that divide disorders into schizophrenia and mood disorders, and (b) evidence suggestive of gene-environment interactions.

Bipolar Disorder↗
PubMed2002

Provisional mapping of quantitative trait loci modulating the acoustic startle response and prepulse inhibition of acoustic startle.

Prepulse inhibition (PPI) of the acoustic startle response (ASR) is a form of sensorimotor gating, defined as an inhibition of the startle response when a low intensity stimulus, the prepulse, precedes the startling stimulus. Deficits in PPI have been reported in schizophrenia and other psychiatric/neurological disorders, and correlate with symptom severity in schizophrenia, suggesting that deficient PPI per se or abnormalities in neural circuits regulating PPI may cause some symptoms of schizophrenia. If so, then genes conferring reduced PPI may contribute toward genetic vulnerability to schizophrenia. Studies with selectively bred rodent strains indicate that PPI is under genetic control; however, the identity of the relevant genes is unknown. The current study used recombinant congenic mouse strains derived from C57BL/6J and A/J parents to assess genetic variability in PPI and in ASR and to identify provisional quantitative trait loci (QTLs) modulating these phenotypes. Significant between-strain differences in ASR and in PPI at each of several prepulse intensities (75, 80, 85, 90, 95 dB) were found. Correlations between PPI at the various prepulse intensities were highly significant, suggesting appreciable overlap in genetic regulation of PPI across prepulse intensities. Five QTLs (chromosomes 3, 5, 7, 16) associated with PPI across all prepulse intensities, but not with ASR, were identified. Two additional QTLs (chromosomes 2, 11) associated with both PPI and ASR were found. Fifteen QTLs were associated with ASR alone. Data on genotypes of informative congenic strains were used to support probable involvement of loci modulating PPI and to narrow the probable chromosomal location of QTLs. If confirmed, these QTLs may suggest candidate genes directing novel mechanisms for regulation of PPI

Acoustic Stimulation↗
PubMed2005

A patient with Rothmund-Thomson syndrome and all features of RAPADILINO.

BACKGROUND: Mutations of the human helicase gene RECQL4 have been identified in a subset of patients with Rothmund-Thomson syndrome (RTS) and in children with the diagnosis of RAPADILINO syndrome (RAdial hypoplasia/aplasia, PAtellar hypoplasia/aplasia, cleft or highly arched PAlate, DIarrhea and DIslocated joints, LIttle size [>2 SDs below the mean in height] and LImb malformation, and slender NOse and NOrmal intelligence). While many features of the 2 genetic disorders overlap, poikiloderma--a hallmark of RTS--has been described as generally absent in RAPADILINO syndrome. OBSERVATIONS: We report herein a patient with RTS who carries a truncating mutation and a newly identified missense mutation of RECQL4. The proband uniquely developed all criteria of RAPADILINO in addition to his prominent skin findings. CONCLUSIONS: Patients with RTS may possess all features of RAPADILINO. Consequently, a genetic approach to RTS and RAPADILINO could be beneficial. This approach may provide a better understanding of the wide variety of related phenotypic findings and improve prognostics.

Abnormalities, Multiple↗
PubMed2004

Clinical features of hereditary spinocerebellar ataxia diagnosed by molecular genetic analysis.

OBJECTIVE: To assess the frequency and clinical features of different types of hereditary spinocerebellar ataxia in Hong Kong. DESIGN: Cross-sectional study using a questionnaire and clinical examination, with the majority of the information retrospectively collected. SETTING: Three regional hospitals, Hong Kong. PARTICIPANTS: All patients with spinocerebellar ataxia that was confirmed by molecular genetic tests between January 2001 and October 2003. MAIN OUTCOME MEASURES: History, latest physical examination results, clinical investigation results, and genetic profiles. RESULTS: A total of 16 Chinese patients had received diagnoses of spinocerebellar ataxia. These patients had spinocerebellar ataxia type 1 (n=3), spinocerebellar ataxia type 3 (Machado-Joseph disease; n=12), and dentatorubro-pallidoluysian atrophy (n=1). The most common manifestation was ataxia (15/16), followed by pyramidal signs (12/16). Other features such as bulbar dysfunction, ophthalmoplegia, neuropathy, and cognitive impairment were present but variable. CONCLUSIONS: The clinical manifestations of different types of spinocerebellar ataxia overlap, and genetic study is necessary to confirm the diagnosis. The frequency of spinocerebellar ataxia type 3 is greater than that of other types among these Chinese patients. The age of onset of this type may correlate inversely with the number of CAG repeats.

Adult↗
PubMed2006

Bipolar II and anxious reactive "comorbidity": toward better phenotypic characterization suitable for genotyping.

OBJECTIVE: In DSM-IV, bipolar II (BP-II) disorder is defined by depression and hypomania. There is little appreciation of affective instability, often associated with anxiety-particularly panic disorder and agoraphobia (PDA)-comorbidity. This association has genetic-familial implications, which we believe must be incorporated in refining the BP-II phenotype suitable for genotyping purposes. METHOD: We examined in a semi-structured format 107 consecutive patients who met DSM-IV criteria for major depressive episode with atypical features and separated them into two subgroups according to the co-occurring criteria for PDA. They were further evaluated on the basis of the Atypical Depression Diagnostic Scale (ADDS), the Hopkins Symptoms Check-list (HSCL 90), and the Hamilton Rating Scale for Depression (HRSD), coupled with its modified form for reverse vegetative features, as well as Axis I and II comorbidity and temperamental dispositions, particularly cyclothymic instability. RESULTS: Fifty (46.7%) of our patients met the DSM-IV criteria for PDA. In terms of significant results, PDA+ was more frequently female, had higher number of hypomanic episodes, and stressors; they were also more often BP-II, and cyclothymic. Ratings of reactivity, somatization, OCD and phobic anxiety too were significantly higher among the PDA+. In related analyses, most AD (75.7%) met criteria for BP-II; the BP-II subgroup was characterized by PDA, as well as borderline personality features and cyclothymic and hyperthymic temperaments. LIMITATIONS: Correlational clinical study in which clinicians could not be kept entirely blind to the variables under investigation. CONCLUSIONS: In line with the description by the French psychiatrist Pierre Kahn a century earlier, cyclothymic reactivity and neurotic features (i.e., atypicality and panic attacks) appear relevant to the definition of what today we consider BP-II disorder. These data, which are in line with current familial-genetic models of this disorder, suggest that the DSM-IV characterization of BP-II must be enriched by greater emphasis on temperamentally based mood and anxious reactivity. Such phenotypic characterization is likely to assist in better genotyping. Previous work by us further suggests the relevance of bulimic and addictive tendencies, as well as "borderline personality" diagnosis in the proband and/or the family. We submit that these conditions, rather than being "comorbid," constitute, along with BP-II, a spectrum of overlapping underlying genetic diatheses.

Adolescent↗
PubMed2004

On the 28-gon symmetry inherent in the genetic code intertwined with aminoacyl-tRNA synthetases--the Lucas series.

Despite considerable efforts it has remained unclear what principle governs the selection of the 20 canonical amino acids in the genetic code. Based on a previous study of the 28-gonal and rotational symmetric arrangement of the 20 amino acids in the genetic code, new analyses of the organization of the genetic code system together with their intrinsic relation to the two classes of aminoacyl-tRNA synthetases are reported in this work. A close inspection revealed how the enzymes and the 20 gene-encoded amino acids are intertwined on the polyhedron model. Complementary and cooperative symmetries between class I and class II aminoacyl-tRNA synthetases displayed by a 28-gon organization are discussed, and we found that the two previously suggested evolutionary axes within the genetic code overlap the symmetry axes within the two classes of aminoacyl-tRNA synthetases. Moreover, it has been shown that the side-chain carbon-atom numbers (2, 1, 3, 4 and 7) in the overwhelming majority of the amino acids recognized by each of the two classes of aminoacyl-tRNA synthetases are determined by a mathematical relationship, the Lucas series. A stepwise co-evolutionary selection logic of the amino acids is manifested by the amino acid side-chain carbon-atom number balance at '17', when grouping the genetic code doublets in the 28-gon organization. The number '17' equals the sum of the initial five numbers in the Lucas series, which are 2, 1, 3, 4 and 7.

Amino Acids↗
PubMed2005

The genetics of schizophrenia and bipolar disorder: dissecting psychosis.

Much work has been done to identify susceptibility genes in schizophrenia and bipolar disorder. Several well established linkages have emerged in schizophrenia. Strongly supported regions are 6p24-22, 1q21-22, and 13q32-34, while other promising regions include 8p21-22, 6q16-25, 22q11-12, 5q21-q33, 10p15-p11, and 1q42. Genomic regions of interest in bipolar disorder include 6q16-q22, 12q23-q24, and regions of 9p22-p21, 10q21-q22, 14q24-q32, 13q32-q34, 22q11-q22, and chromosome 18. Recently, specific genes or loci have been implicated in both disorders and, crucially, replicated. Current evidence supports NRG1, DTNBP1, DISC1, DAOA(G72), DAO, and RGS4 as schizophrenia susceptibility loci. For bipolar disorder the strongest evidence supports DAOA(G72) and BDNF. Increasing evidence suggests an overlap in genetic susceptibility across the traditional classification systems that dichotomised psychotic disorders into schizophrenia or bipolar disorder, most notably with association findings at DAOA(G72), DISC1, and NRG1. Future identification of psychosis susceptibility genes will have a major impact on our understanding of disease pathophysiology and will lead to changes in classification and the clinical practice of psychiatry.

Bipolar Disorder↗
PubMed2005

Endogenous retroviruses and animal reproduction.

Endogenous retroviruses (ERV), as part of the host genetic heritage, are transmissible to the next generation in a Mendelian way. Their abundance in animal genomes and their expression primarily detected in germ cells, embryonic tissues and cancer cell lines, raised the question of their biological significance. This article reviews the possible role of ERVs in the physiology and diseases of animal reproduction, from Drosophila to human. In males, there is no trivial involvement of ERVs in a physiological process. Conversely, a spermatogenesis defect was associated in the human male with HERV-K expression and HERV15-induced chromosomal alteration, leading to cancer and infertility, respectively. In females, the study of insect ERVs (IERV) pointed out the overlap between genetics and virology with the genetic-dependent regulation of ZAM and the non-infectious and infectious life cycles of gypsy. The pattern of ERVs expression in rodent, ovine and human females suggest a hormone-dependent mechanism consistent with the mammalian oestrus cycle regulation. The differentiation of the mammary epithelium and breast tumorigenesis involving the mouse mammary tumour viruses (MMTV) illustrate the intimate connection between endogenous and exogenous retroviruses. Last, as a major site of ERVs transcription, placenta contributed to our understanding of ERVs modulation of neighbouring gene expression. As an interface, i.e. a site of conflicts and exchanges, placenta should resist infection and protect the foetus against the maternal immune system. Retroviral envelopes could theoretically provide such features due to receptor interference, immunosuppression and fusion properties, as shown by the HERV-W envelope involved in the syncytiotrophoblast formation. We conclude with an insight on the evolutionary and epigenetic consequences of the relationships of ERV guests with their animal hosts.

Animals↗
PubMed1996

Genetic mapping of quantitative trait loci controlling growth and wood quality traits in Eucalyptus grandis using a maternal half-sib family and RAPD markers.

Quantitative trait loci (QTL) mapping of forest productivity traits was performed using an open pollinated half-sib family of Eucalyptus grandis. For volume growth, a sequential QTL mapping approach was applied using bulk segregant analysis (BSA), selective genotyping (SG) and cosegregation analysis (CSA). Despite the low heritability of this trait and the heterogeneous genetic background employed for mapping, BSA detected one putative QTL and SG two out of the three later found by CSA. The three putative QTL for volume growth were found to control 13.7% of the phenotypic variation, corresponding to an estimated 43.7% of the genetic variation. For wood specific gravity five QTL were identified controlling 24.7% of the phenotypic variation corresponding to 49% of the genetic variation. Overlapping QTL for CBH, WSG and percentage dry weight of bark were observed. A significant case of digenic epistasis was found, involving unlinked QTL for volume. Our results demonstrate the applicability of the within half-sib design for QTL mapping in forest trees and indicate the existence of major genes involved in the expression of economically important traits related to forest productivity in Eucalyptus grandis. These findings have important implications for marker-assisted tree breeding.

Chromosome Mapping↗
PubMed1976

Biogenesis of mitochondria 44. comparative studies and mapping of mitochondrial oligomycin resistance mutations in yeast based on gene recombination and petite deletion analysis.

A comparative study of eight independently isolated mitochondrial oligomycin resistant mutants obtained from three laboratories show a variety of phenotypes based on cross resistance to venturicidin and sensitivity to low temperature. Analysis of recombination between pairs of markers indicate the existence of at least three genetic classes; class A, cross resistant to venturicidin and including the mutations OIII, [olil-r], [olgi-R], [tso-r]; class B, mutations OI, [olil7-r], [OLG2-R]; and class C, the mutation O11. The recombination data is consistent with mutations of each class residing in three separate genes, although mutations of class A and B show very close linkage. Recombination in non-polar crosses had demonstrated that markers of all three classes are linked to the mikl locus in the configuration (AB)-mikl-C. The mapping of this segment with respect to other markers of the mitochondrial genome and the order of classes A and B was established by analysis of co-retention frequenceis of markers in primary petite isolates as well as by analysis of marker overlap of genetically and physically defined petite genomes. The unambiguous order eryl-A-B-mik1-C-par was obtained. DNA-DNA hybridization studies using mtDNA isolated from selected petites confirms this map and estimates the physical separation of markers. A resonable correlation exists in this region of th genome between distances estimated physically by hybridization and genetically by frequencey of recombination in non-polar crosses. It is potulated that the oligomycin-mikamycin linkage group represents a cluster of genes involved in determing a number of mitochondrial membrane proteins associated with the mitochondrial ATPase and respiratory complex III.

DNA, Mitochondrial↗
PubMed2000

Genetic evidence of distinct physiological regulation mechanisms in the sigma(54) Pu promoter of Pseudomonas putida.

The activity of the toluene-responsive sigma(54) Pu promoter of the pWW0 TOL plasmid of Pseudomonas putida is down-regulated in vivo during exponential growth in rich medium and also by the presence of glucose in the culture. Although the Pu promoter already performs poorly during log growth in minimal medium when amended with casamino acids, the addition of glucose further decreased by two- to threefold the accumulation of beta-galactosidase in a Pu-lacZ reporter P. putida strain. Since Pu was still down-regulated during exponential growth regardless of glucose addition, it appeared that the carbohydrate separately influenced promoter activity. This notion was supported by the growth-dependent induction pattern of Pu in a ptsN mutant of P. putida, the loss of which makes Pu no longer responsive to repression by glucose. On the other hand, overexpression of the sigma factor sigma(54), known to partially alleviate the exponential silencing of the promoter, did not affect glucose inhibition of Pu. These data indicated that exponential silencing and carbon source-dependent repression are two overlapping but genetically distinguishable mechanisms that adapt Pu to the physiological status of the cells and nutrient availability.

Culture Media↗
PubMed1997

Hereditary motor and sensory neuropathy IIB: clinical and electrodiagnostic characteristics.

Axonal forms of autosomal dominant hereditary motor and sensory neuropathies (HMSNs) represent a heterogeneous group of disorders based on genetic linkage studies. We recently identified one large family with axonal HMSN exhibiting linkage to chromosome 3q, designated HMSN IIB, and report here the clinical and electrodiagnostic features. We clinically evaluated 10 individuals with HMSN IIB and performed detailed electrophysiologic studies in 5 of these patients. HMSN IIB is characterized clinically by the presence of distal symmetric motor weakness and prominent sensory loss affecting the lower extremities with preserved ankle reflexes. Symptomatic age at onset is in the second or early third decade of life. Six patients with HMSN IIB had distal trophic ulcerations in the feet, leading to eventual toe amputations in four cases. Electrodiagnostic studies confirmed a distal sensorimotor axonopathy involving the lower limbs with normal motor conduction velocities. Tibial H-reflexes were preserved in HMSN IIB, despite the uniform loss of sural nerve potentials. Overall, individuals with HMSN IIB demonstrated a consistent clinical and electrodiagnostic phenotype that had no overlap with genetically unaffected family members. The identification of specific clinical and electrodiagnostic features of HMSN IIB may prove useful in the diagnosis and differentiation between various subtypes of HMSN II.

Adult↗
PubMed2004

Genetics of familial combined hyperlipidemia and risk of coronary heart disease.

Coronary heart disease is the leading cause of death in developed countries. This alarming statistic is partly attributable to lifestyle, and partly due to the genetic factors that make humans highly susceptible to atherosclerotic vascular disease. The principal metabolic causes of atherosclerosis include hyperlipidemia, hypertension, obesity, insulin resistance and diabetes mellitus. Here we discuss the aetiology of familial combined hyperlipidemia (FCHL), a highly atherogenic disorder affecting 1-2% of the Western world. Genome-wide linkage studies indicate that more than three genes contribute to the pernicious lipid profile of FCHL, and that these genes reside within the 1q21-23, 11p14.1-q12.1 and 16q22-24.1 chromosomal regions. Other loci include 1p31, 6q16.1-16.3 and 8p23.3-22, but the linkage data for these are not yet persuasive. Combined linkage and association analyses provide compelling evidence for the involvement of two distinct alleles at the APOA1/C3/A4/A5 gene cluster in the transmission of FCHL. An important lesson arising from the study of a complex genetic disorder, such as FCHL, that lacks a consensus on diagnostic criteria, is that an understanding of complex genetic disorders can derive from comparative analyses of genome-wide linkage data generated from conditions that share phenotypic overlap. The identification of potential genetic overlap between FCHL and the Metabolic Syndrome, which is estimated to affect 47 million Americans, promises to deliver new targets for reducing the risk of important conditions such as cardiovascular disease and stroke.

Alleles↗
PubMed2002

Comparison of clinicopathologic characteristics and genetic alterations between microsatellite instability-positive and microsatellite instability-negative sporadic colorectal carcinomas in patients younger than 40 years old.

PURPOSE: Many studies have demonstrated that sporadic microsatellite instability-positive colorectal cancers share several clinicopathologic features with hereditary nonpolyposis colorectal cancers, including right-sided location, young age of onset, characteristic histomorphologic features, and a good prognosis. The aim of this study was to define distinct clinicopathologic features of sporadic microsatellite instability-positive colorectal cancers and to compare genotypic characteristics between microsatellite instability-positive and microsatellite instability-negative colorectal cancers in a young group. METHODS: We analyzed 61 cases of young patients (<40 years old) with colorectal cancers for microsatellite instability at five mononucleotide and three dinucleotide repeats, loss of heterozygosity at APC and DCC, and K-ras and p53 mutations. Microsatellite instability status was correlated with molecular genetic factors and clinicopathologic parameters. RESULTS: Microsatellite instability positivity was detected in 19 (31.1 percent) of 61 cases. Allelic alterations in TGFbetaRII, BAX, and IGFIIR were observed exclusively in microsatellite instability-positive tumors (63.1, 26.3, and 26.3 percent, respectively). Microsatellite instability-positive tumors exhibited a lower frequency of the p53 mutation (10.5 percent) than microsatellite instability-negative tumors (47.6 percent; P < 0.05). However, microsatellite instability status was not associated with APC or DCC allelic deletion or with the K-ras mutation. Microsatellite instability-positive colorectal cancers exhibited a proclivity toward proximal location, expansive growth pattern, and large tumor size (P < 0.05). Microsatellite instability-positive colorectal cancers had lower preoperative serum carcinoembryonic antigen levels (P < 0.05), a less advanced stage at presentation (P < 0.05), and a tendency toward better prognosis (P = 0.051) than microsatellite instability-negative colorectal cancers. However, there was no difference between microsatellite instability-positive and microsatellite instability-negative colorectal cancers regarding gross features, tumor grade, and extracellular mucin production. CONCLUSION: These results suggest that sporadic microsatellite instability-positive colorectal cancers in young patients have different histomorphologic features from microsatellite instability-negative colorectal cancers and hereditary nonpolyposis colorectal cancers, some overlap of genetic alterations on multistep carcinogenesis with microsatellite instability-negative colorectal cancers, and a tendency for better prognosis.

Adult↗
PubMedDate not supplied

Family and genetic studies of indices of insulin sensitivity and insulin secretion in Pima Indians.

BACKGROUND: The present analyses were conducted to examine the extent to which insulin sensitivity and insulin secretion, assessed using simple indices derived from an oral glucose tolerance test, are influenced by genetic factors, and to assess whether these genetic factors overlap with those influencing susceptibility to type 2 diabetes in Pima Indians. METHODS: Indices calculated from fasting and 2-h post-load insulin (I(0), I(120)) and glucose (G(0), G(120)) concentrations included insulin sensitivity index [ISI(0)=10(4)/(I(0).G(0))] and corrected insulin response [CIR(120)=I(120)/[G(120).(G(120)-70 mg/dl)]]. Heritability (h(2)) was determined using variance components methods in 1421 non-diabetic individuals from 446 sibships. Among 595 individuals in 186 sibships, genome-wide quantitative trait linkage analyses of ISI(0) and CIR(120) were conducted and affected-sibling analyses of diabetic siblings stratified by prediabetic measurements of ISI(0) and CIR(120) were also performed. RESULTS: Both ISI(0) (h(2)=0.37+/-0.06) and CIR(120) (h(2)=0.25+/-0.07) were moderately heritable. Modest evidence for linkage with CIR(120) (logarithm of odds (LOD)=1.6) was observed on chromosome 1q in a region previously shown to have linkage with young-onset diabetes in Pimas. When diabetic siblings were stratified by CIR(120), evidence for linkage in this region was strongest (LOD=1.5) among those with a low CIR(120). Additional regions with modest evidence for linkage with ISI(0) were observed on chromosomes 9p (LOD=2.0) and 14p (LOD=1.7). CONCLUSIONS: The present analyses suggest that insulin sensitivity and insulin secretion are influenced by genetic factors in Pima Indians. The linkage analyses suggest that the putative diabetes-susceptibility gene on chromosome 1q affects insulin secretion. Published in 2001 by John Wiley & Sons, Ltd.

Arizona↗
PubMed2005

How genetics research in Parkinson's disease is enhancing understanding of the common idiopathic forms of the disease.

PURPOSE OF REVIEW: Rapid progress in genetics has meant that there are now five genes identified for 'Parkinson's disease'. The detailed phenotypes vary, but generally the dominant genes cause a Lewy body disease spectrum whereas recessive genes cause a milder parkinsonism with variable inclusion body pathology. The subject of this review is to highlight these discoveries and to discuss their relationships to idiopathic Parkinson's disease. RECENT FINDINGS: In January 2004, mutations in PINK1, coding for a mitochondrial kinase, were found to be causal for recessive parkinsonism. Subsequently, several studies have found additional mutations associated with early onset parkinsonism. Some cases have been described with a phenotype much closer to idiopathic Parkinson's disease, but it does not appear that PINK1 is a major risk factor for the sporadic disease. Later in the same year, the LRRK2 gene was shown to cause a dominant disease with a broader phenotype. The protein product was named dardarin and contains GTPase and kinase domains. Lewy bodies have been reported in LRRK2 cases, potentially linking this gene with sporadic Parkinson's disease. One mutation, G2019S, is found in a significant percentage of cases, including sporadic Parkinson's disease. SUMMARY: Mutations in these two genes, along with previously described Mendelian variants, are beginning to yield important information about loss of specific neuronal groups or to protein inclusion pathology. How this relates to sporadic Parkinson's disease, however, is not yet fully defined. There are clear phenotypic overlaps with genetic and sporadic Parkinson's disease, especially for the dominant genes, suggesting that common facets of pathogenesis may exist.

Humans↗