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11.
12.
Progress in the autosomal segmental aneusomy syndromes (SASs): single or multi-locus disorders? 总被引:3,自引:2,他引:3
Based on cytogenetic observations, several syndromes have been previously
identified as microdeletion-based disorders. In this review, recent
progress is presented regarding whether one or multiple genes can be
implicated in the pathogenesis of these segmentally aneusomic syndromes.
The syndromes discussed include Angelman, Alagille, Williams,
Langer-Giedeon, Prader-Willi, Smith-Magenis, Miller-Dieker, and
DiGeorge/velocardiofacial or the 22q11 deletion syndromes. For Angelman and
Alagille syndromes, single genes have been identified, whereas for Williams
and Langer-Giedion syndromes, more than one gene can be implicated.
Although there has been significant progress in dissecting the molecular
basis for the other disorders, the ultimate answer regarding one versus
several genes remains to be determined.
相似文献
13.
Missense mutation in a von Willebrand factor type A domain of the alpha 3(VI) collagen gene (COL6A3) in a family with Bethlem myopathy 总被引:2,自引:0,他引:2
Pan TC; Zhang RZ; Pericak-Vance MA; Tandan R; Fries T; Stajich JM; Viles K; Vance JM; Chu ML; Speer MC 《Human molecular genetics》1998,7(5):807-812
The Bethlem myopathy is a rare autosomal dominant proximal myopathy
characterized by early childhood onset and joint contractures. Evidence for
linkage and genetic heterogeneity has been established, with the majority
of families linked to 21q22.3 and one large family linked to 2q37,
implicating the three type VI collagen subunit genes, COL6A1 (chromosome
21), COL6A2 (chromosome 21) and COL6A3 (chromosome 2) as candidate genes.
Mutations of the invariant glycine residues in the triple-helical
domain-coding region of COL6A1 and COL6A2 have been reported previously in
the chromosome 21-linked families. We report here the identification of a
G-->A mutation in the N-terminal globular domain-coding region of COL6A3
in a large American pedigree (19 affected, 12 unaffected), leading to the
substitution of glycine by glutamic acid in the N2 motif, which is
homologous to the type A domains of the von Willebrand factor. This
mutation segregated to all affected family members, to no unaffected family
members, and was not identified in 338 unrelated Caucasian control
chromosomes. Thus mutations in either the triple-helical domain or the
globular domain of type VI collagen appear to cause Bethlem myopathy.
相似文献
14.
doublecortin is the major gene causing X-linked subcortical laminar heterotopia (SCLH) 总被引:12,自引:0,他引:12
des Portes V; Francis F; Pinard JM; Desguerre I; Moutard ML; Snoeck I; Meiners LC; Capron F; Cusmai R; Ricci S; Motte J; Echenne B; Ponsot G; Dulac O; Chelly J; Beldjord C 《Human molecular genetics》1998,7(7):1063-1070
Subcortical laminar heterotopia (SCLH), or 'double cortex', is a cortical
dysgenesis disorder associated with a defect in neuronal migration.
Clinical manifestations are epilepsy and mental retardation. This disorder,
which mainly affects females, can be inherited in a single pedigree with
lissencephaly, a more severe disease which affects the male individuals.
This clinical entity has been described as X- SCLH/LIS syndrome. Recently
we have demonstrated that the doublecortin gene, which is localized on the
X chromosome, is implicated in this disorder. We have now performed a
systematic mutation analysis of doublecortin in 11 unrelated females with
SCLH (one familial and 10 sporadic cases) and have identified mutations in
10/11 cases. The sequence differences include nonsense, splice site and
missense mutations and these were found throughout the gene. These results
provide strong evidence that loss of function of doublecortin is the major
cause of SCLH. The absence of phenotype-genotype correlations suggests that
X-inactivation patterns of neuronal precursor cells are likely to
contribute to the variable clinical severity of this disorder in females.
相似文献
15.
16.
Interchromosomal duplications of the adrenoleukodystrophy locus: a phenomenon of pericentromeric plasticity 总被引:13,自引:5,他引:13
Eichler EE; Budarf ML; Rocchi M; Deaven LL; Doggett NA; Baldini A; Nelson DL; Mohrenweiser HW 《Human molecular genetics》1997,6(7):991-1002
A 9.7 kb segment encompassing exons 7-10 of the adrenoleukodystrophy (ALD)
locus of the X chromosome has duplicated to specific locations near the
pericentromeric regions of human chromosomes 2p11,10p11, 16p11 and 22q11.
Comparative sequence analysis reveals 92-96% nucleotide identity,
indicating that the autosomal ALD paralogs arose relatively recently during
the course of higher primate evolution (5-10 million years ago). Analysis
of sequences flanking the duplication region identifies the presence of an
unusual GCTTTTTGC repeat which may be a sequence-specific integration site
for the process of pericentromeric- directed transposition. The breakpoint
sequence and phylogenetic analysis predict a two-step transposition model,
in which a duplication from Xq28 to pericentromeric 2p11 occurred once,
followed by a rapid distribution of a larger duplicon cassette among the
pericentromeric regions. In addition to facilitating more effective
mutation detection among ALD patients, these findings provide further
insight into the molecular basis underlying a pericentromeric-directed
mechanism for non- homologous interchromosomal exchange.
相似文献
17.
Human mini-chromosomes in mouse embryonal stem cells 总被引:3,自引:2,他引:3
We have introduced human mini-chromosomes of 4 Mb and approximately 15 Mb
in size into mouse embryonal stem cells. Although these human mini-
chromosomes are stable in hamster and chicken cells, they re-arrange or
segregate aberrantly in the embryonal stem cells and are rapidly lost in
the absence of selection. However, one of the mini-chromosomes re-
arranged, acquired mouse centromeric sequences and was then stably
maintained for at least 60 population doublings in culture. This mini-
chromosome, which is 4 Mb in size, is a candidate for a mouse germ line
chromosome vector.
相似文献
18.
Louise R Rodino-Klapac Paul ML Janssen Chrystal L Montgomery Brian D Coley Louis G Chicoine K Reed Clark Jerry R Mendell 《Journal of translational medicine》2007,5(1):45-11
Background
Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder with monogenic mutations setting the stage for successful gene therapy treatment. We have completed a study that directly deals with the following key issues that can be directly adapted to a gene therapy clinical trial using rAAV considering the following criteria: 1) A regional vascular delivery approach that will protect the patient from widespread dissemination of virus; 2) an approach to potentially facilitate safe passage of the virus for efficient skeletal muscle transduction; 3) the use of viral doses to accommodate current limitations imposed by vector production methods; 4) and at the same time, achieve a clinically meaningful outcome by transducing multiple muscles in the lower limb to prolong ambulation. 相似文献19.
Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations 总被引:9,自引:1,他引:9
Meyer J; Sudbeck P; Held M; Wagner T; Schmitz ML; Bricarelli FD; Eggermont E; Friedrich U; Haas OA; Kobelt A; Leroy JG; Van Maldergem L; Michel E; Mitulla B; Pfeiffer RA; Schinzel A; Schmidt H; Scherer G 《Human molecular genetics》1997,6(1):91-98
It has previously been shown that, in the heterozygous state, mutations in
the SOX9 gene cause campomelic dysplasia (CD) and the often associated
autosomal XY sex reversal. In 12 CD patients, 10 novel mutations and one
recurrent mutation were characterized in one SOX9 allele each, and in one
case, no mutation was found. Four missense mutations are all located within
the high mobility group (HMG) domain. They either reduce or abolish the
DNA-binding ability of the mutant SOX9 proteins. Among the five nonsense
and three frameshift mutations identified, two leave the C-terminal
transactivation (TA) domain encompassing residues 402-509 of SOX9 partly or
almost completely intact. When tested in cell transfection experiments, the
recurrent nonsense mutation Y440X, found in two patients who survived for
four and more than 9 years, respectively, exhibits some residual
transactivation ability. In contrast, a frameshift mutation extending the
protein by 70 residues at codon 507, found in a patient who died shortly
after birth, showed no transactivation. This is apparently due to
instability of the mutant SOX9 protein as demonstrated by Western blotting.
Amino acid substitutions and nonsense mutations are found in patients with
and without XY sex reversal, indicating that sex reversal in CD is subject
to variable penetrance. Finally, none of 18 female patients with XY gonadal
dysgenesis (Swyer syndrome) showed an altered SOX9 banding pattern in SSCP
assays, providing evidence that SOX9 mutations do not usually result in XY
sex reversal without skeletal malformations.
相似文献
20.
Two types of phantoms were developed with which to evaluate the overall performance of digital subtraction angiography (DSA) systems. A dynamic phantom, called a "fish bone" phantom, consists of polyethylene tubes that simulate blood vessels with various lesions, such as stenoses, ulcers, and aneurysms. With this phantom, washout curves were obtained representing the relationship between iodine content and time. It will be useful for qualitative assessment of DSA images, evaluation of different image-processing schemes, and studies of blood flow analysis. A static phantom, called a "C-D" phantom, can be used for measurement of quantitative contrast-detail (C-D) diagrams and for daily monitoring of DSA systems. This was constructed of tubes of seven different diameters (2.15-0.28 mm) and 14 different concentrations of contrast medium (100%-1.1% Renografin-76 [meglumine and sodium diatrizoate]). The C-D diagrams were determined from an observer performance study using C-D phantom images obtained at four different DSA settings. 相似文献