Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Miller-Dieker syndrome (MDS) is a multiple malformation syndrome characterized by classical lissencephaly and a characteristic facies. It is associated with visible or submicroscopic deletions within chromosome band 17p13.3. Lissencephaly without facial dysmorphism has also been observed and is referred to as isolated lissencephaly sequence (ILS). Apparently partial and non-overlapping deletions of the 5' or 3' end of a candidate gene LIS1 in one ILS and one MDS patient had suggested that MDS was a single gene disorder, and that LIS1 spans in excess of 400 kb. However, the originally presumed 5' end of LIS1 was found to belong to the 14-33 epsilon gene residing more distally on 17p13.3. We have now isolated the correct 5' end of LIS1, constructed a approximately 500 kb genomic contig encompassing LIS1, and estimated its gene to be approximately 80 kg. Fluorescence in situ hybridization analysis of an ILS patient with a de novo balanced translocation, as well as analysis of several other key MDS and ILS deletion patients, localizes the lissencephaly critical region within the LIS1 gene. Therefore, LIS1 remains the strongest candidate gene for the lissencephaly phenotype in ILS and MDS. Our analyses also suggest that additional genes distal to LIS1 may be responsible for the facial dysmorphology and other abnormalities seen in MDS but not in ILS patients, supporting our original concept MDS as a contiguous gene deletion syndrome.
Hum Mol Genet 1997 Feb
PMID:A revision of the lissencephaly and Miller-Dieker syndrome critical regions in chromosome 17p13.3. 906 34

Classical lissencephaly (smooth brain) or generalized agyria-pachygyria is a severe brain malformation which results from an arrest of neuronal migration at 9-13 weeks gestation. It has been observed in several malformation syndromes including Miller-Dieker syndrome (MDS) and isolated lissencephaly sequence (ILS). A gene containing beta-transducin like repeats, now known as LIS1, was previously mapped to the ILS/MDS chromosome region on 17p13.3. We recently localized the classical lissencephaly critical region to the LIS1 gene locus by molecular analysis of key ILS and MDS patients. We have now characterized the structure of LIS1, which consists of 11 exons, and have searched for the presence of subtle mutations in 19 ILS patients who showed no gross rearrangements of LIS1. Single strand conformational polymorphism (SSCP) analysis revealed band-shifts for three patients, each involving a different coding exon, which were not observed in their respective parental DNAs. Sequence analysis identified these de novo mutations as dA --> dG transition in exon VI at nucleotide 446, a dC --> dT transition in exon VIII at nucleotide 817, and a 22 bp deletion at the exon IX-intron 9 junction from nucleotide 988 to 1,002+7, which causes skipping of exon IX in the mature LIS1 transcript. These changes are predicted to result in an H149R amino acid substitution, an R273X premature translation termination, and abolition of amino acids 301-334, in the respective LIS1 proteins. These data thus confirm LIS1 as the gene responsible for classical lissencephaly in ILS and MDS.
Hum Mol Genet 1997 Feb
PMID:Point mutations and an intragenic deletion in LIS1, the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome. 906 35

Subcortical band heterotopia (SBH) and classical lissencephaly (LIS) result from deficient neuronal migration which causes mental retardation and epilepsy. A single LIS/SBH locus on Xq22.3-q24 was mapped by linkage analysis and physical mapping of the breakpoint in an X;2 translocation. A recently identified gene, doublecortin ( DCX ), is expressed in fetal brain and mutated in LIS/SBH patients. We have identified four novel missense mutations in the gene, one familial mutation with LIS in a male and SBH in the carrier females, one de novo mutation in an SBH female, and two mutations in sporadic SBH female patients. The DCX gene is found to be expressed exclusively at a very high level in the adult frontal lobe. We have also cloned the X-linked mouse doublecortin (Dcx) gene. It encodes isoforms of a highly hydrophilic 40 kDa protein, homologous to its human counterpart and containing several potential phosphorylation sites. Both human and mouse DCX proteins are homologous to a CNS protein containing a Ca2+/calmodulin kinase domain, suggesting that the DCX protein may belong to a novel class of intracellular proteins involved in neuronal migration through Ca2+-dependent signaling.
Hum Mol Genet 1998 Aug
PMID:Human doublecortin (DCX) and the homologous gene in mouse encode a putative Ca2+-dependent signaling protein which is mutated in human X-linked neuronal migration defects. 966 76

The human gene HIC1 (hypermethylated in cancer) maps to chromosome 17p13.3 and is deleted in the contiguous gene disorder Miller-Dieker syndrome (MDS) [Makos-Wales et al. (1995) Nature Med., 1, 570-577; Chong et al. (1996) Genome Res., 6, 735-741]. We isolated the murine homologue Hic1, encoding a zinc-finger protein with a poxvirus and zinc-finger (POZ) domain and mapped it to mouse chromosome 11 in a region exhibiting conserved synteny to human chromosome 17. Comparison of genomic and cDNA sequences predicts two exons for the murine Hic1. The second exon exhibits 88% identity to the human HIC1 on DNA level. During embryonic development, Hic1 is expressed in mesenchymes of the sclerotomes, lateral body wall, limb and cranio-facial regions embedding the outgrowing peripheral nerves during their differentiation. During fetal development, Hic1 additionally is expressed in mesenchymes apposed to precartilaginous condensations, at many interfaces to budding epithelia of inner organs, and weakly in muscles. We observed activation of Hic1 expression in the embryonic anlagen of many tissues displaying anomalies in MDS patients. Besides lissencephaly, MDS patients exhibit facial dysmorphism and frequently additional birth defects, e.g. anomalies of the heart, kidney, gastrointestinal tract and the limbs (OMIM 247200). Thus, HIC1 activity may correlate with the defective development of the nose, jaws, extremities, gastrointestinal tract and kidney in MDS patients.
Hum Mol Genet 1999 Apr
PMID:Isolation and embryonic expression of the novel mouse gene Hic1, the homologue of HIC1, a candidate gene for the Miller-Dieker syndrome. 1007 40

Using polymerase chain reaction (PCR), we examined a panel of 10 microsatellite markers (BAT26, BAT40, D2S123, D4S171, D8S87, D10S197, D12S89, Tp53, D18S58, PLCpr) covering nine chromosomal arms for microsatellite instability (MSI) in 29 patients with primary MDS. Bone marrow DNA was compared with corresponding constitutional DNA derived from buccal epithelial cells. Apart from BAT26 and BAT40 that were mononucleotide (poly A) repeats, the others were dinucleotide (CA) repeats. The patients comprised 10 cases of refractory anemia (RA), three cases of refractory anemia with ringed sideroblasts (RARS), nine cases of refractory anemia with excess of blasts (RAEB), four cases of refractory anemia with excess of blasts in transformation (RAEBt), and three cases of chronic myelomonocytic leukemia (CMML). Serial samples were available in seven patients, in which four showed transformation into higher disease grade or acute myeloid leukemia (AML). Genetic alterations at one locus (three at D2S123, one at D4S171) were evident in four cases, and loss of heterozygosity at Tp53 was detected in one case. Accordingly, none of the 29 patients with primary MDS nor the seven with disease progression in this study exhibited MSI. This shows that MSI may not be important in the pathogenesis or progression of MDS in contrast to other genetic mechanisms, notably recurrent chromosomal abnormalities that dysregulate the expression or function of genes controlling cell growth, differentiation and apoptosis.
Int J Mol Med 2000 Feb
PMID:Absence of microsatellite instability in primary myelodysplastic syndrome. 1063 95

HIC1 is a candidate tumor suppressor gene which is frequently hypermethylated in human tumors, and its location within the Miller-Dieker syndrome's critical deletion region at chromosome 17p13.3 makes it a candidate gene for involvement in this gene deletion syndrome. To study the function of murine Hic1 in development, we have created Hic1 -deficient mice. These animals die perinatally and exhibit varying combinations of gross developmental defects throughout the second half of development, including acrania, exencephaly, cleft palate, limb abnormalities and omphalocele. These findings demonstrate a role for Hic1 in the development of structures affected in the Miller-Dieker syndrome, and provide functional evidence to strengthen its candidacy as a gene involved in this disorder.
Hum Mol Genet 2000 Feb 12
PMID:Mice deficient in the candidate tumor suppressor gene Hic1 exhibit developmental defects of structures affected in the Miller-Dieker syndrome. 1065 51

Magnetic resonance imaging is now used routinely in the evaluation of developmental and neurological disorders and provides exquisite images of the living human brain. Consequently, it is evident that cortical malformations are more common than previously thought. Among the most severe is classical lissencephaly, in which the cortex lacks the complex folding that characterizes the normal human brain. Lissencephaly includes agyria and pachygyria, and merges with subcortical band heterotopia. Current molecular genetic techniques combined with the identification of affected patients have enabled the detection of two of the genes responsible: LIS1 (PAFAH1B1) on chromosome 17 and DCX (doublecortin) on the X chromosome. This review highlights the discovery of these genes and discusses the advances made in understanding the molecular basis of cortical development and improvements in diagnosis and genetic counseling.
Mol Med Today 2000 Jul
PMID:Lissencephaly and subcortical band heterotopia: molecular basis and diagnosis. 1085 64

Lissencephaly is a cortical malformation secondary to impaired neuronal migration resulting in mental retardation, epilepsy and motor impairment. It shows a severity spectrum from agyria with a severely thickened cortex to posterior band heterotopia only. The LIS1 gene on 17p13.3 encodes a 45 kDa protein named PAFAH1B1 containing seven WD40 repeats. This protein is required for optimal neuronal migration by two proposed mechanisms: as a microtubule-associated protein and as one subunit of the enzyme platelet-activating factor acetylhydrolase. Approximately 65% of patients with isolated lissencephaly sequence (ILS) show intragenic mutations or deletions of the LIS1 gene. We analyzed 29 non-deletion ILS patients carrying a mutation of LIS1 and we report 15 novel mutations. Patients with missense mutations had a milder lissencephaly grade compared with those with mutations leading to a shortened or truncated protein (P = 0.022). Early truncation/deletion mutations in the putative microtubule-binding domain resulted in a more severe lissencephaly than later truncation/deletion mutations (P < 0.001). Our results suggest that the lissencephaly severity in ILS caused by LIS1 mutations may be predicted by the type and location of the mutation. Using a spectrum of ILS patients, we confirm the importance of specific WD40 repeats and a putative microtubule-binding domain for PAFAH1B1 function. We suggest that the small number of missense mutations identified may be due to underdiagnosis of milder phenotypes and hypothesize that the greater lissencephaly severity seen in Miller-Dieker syndrome may be secondary to the loss of another cortical development gene in the deletion of 17p13.3.
Hum Mol Genet 2000 Dec 12
PMID:The location and type of mutation predict malformation severity in isolated lissencephaly caused by abnormalities within the LIS1 gene. 1111 46

Initial combinatorial library designs were based on 2D substituent properties. Subsequently, two important extensions were introduced to improve the approach: use of pharmacophores to introduce 3D information, and performing calculations on the enumerated library products rather than just on the substituents. Unfortunately, practical compromises due to the large number of possible products, the large number of conformations per product, and the explicit dependence on the scaffold limit the application of these extensions in five important ways: (1) to small virtual libraries, (2) to only 3- or 4-point pharmacophores, (3) to inadequate conformational sampling, (4) to simplistic diversity measures, and (5) to requiring a complete new calculation for every new library. The 3D oriented substituent pharmacophores have been developed to overcome these limitations. These add two additional points and corresponding distances to each substituent pharmacophore. This adds little additional computation beyond a normal 3D pharmacophore calculation on the substituents, but recaptures most of the orienting information lost in breaking up the enumerated products into fragments. Two main approximations are still implicitly required: the combinatorial conformer assumption and the template alignment assumption. In turn, however, they are designed to account not just for the 3- and 4-point pharmacophores, but for pharmacophores with up to 9 points in enumerated products with three sites of diversity. Perhaps more importantly, pharmacophore calculations are shown to be very sensitive to conformational sampling. The small number of substituents, plus the small number of rotatable bonds per substituent, permits very thorough conformational sampling. For a rigid scaffold with three diversity sites of 1,000 candidate substituents each, the number of molecules to analyze is reduced by a factor of 10(6), and the number of conformations per molecule is reduced by another 10(4). In addition, the modest number of pairwise substituent similarities permits the creation of a Euclidean property space by MDS. This allows for sophisticated experimental design methods that require coordinates, rather than just the counting of the number of set bits in a library union fingerprint. Finally, oriented substituent calculations are scaffold independent and transferable. They can be stored in a database and need not be repeated for every new library. Thus, there are some approximations in the correspondence between oriented substituent pharmacophore similarities and enumerated product pharmacophore similarities. However, these errors are minor compared to the five advantages that the new method enables: large virtual library sizes, thorough conformational sampling, accounting for 1- to 9-point pharmacophores, creation of a Euclidean property space, and a reusable database of precomputed substituent values.
J Mol Graph Model
PMID:Oriented substituent pharmacophore PRopErtY space (OSPPREYS): a substituent-based calculation that describes combinatorial library products better than the corresponding product-based calculation. 1114 57

The 102-T/C polymorphism of the 5-HT(2A) receptor gene was analysed in 159 patients with major depression and 164 unrelated and healthy controls using a case-control design. Allele and genotype frequencies did not differ between cases and controls. No differences according to sex, age of onset, melancholia, suicidal behaviour or family history of psychiatric illness were found. However, genotype distributions significantly differed between patients with seasonal pattern in their episodes (MDS) and patients with no seasonal pattern (N-MDS) (chi(2) = 10.63; P = 0.004). A seasonal pattern was 7.57 times more frequent in 102C-allele carriers than in 102T homozygous (95.1% of patients MDS carried 102C-allele vs 72% of patients N-MDS (chi(2) = 9.45, df=1, P = 0.002; OR = 7.57 (95% CI: 1.65--48.08)). These results suggest that variation in the 5-HT2A receptor gene may play a role in the development of major depression with seasonal pattern and support the existence of a genetic and etiological heterogeneity underlying the diagnosis of major depression.
Mol Psychiatry 2001 Mar
PMID:Variability in the 5-HT(2A) receptor gene is associated with seasonal pattern in major depression. 1131 30


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