Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0025362 (mental retardation)
15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Disorders known to be caused by molecular and cytogenetic abnormalities of the proximal short arm of chromosome 17 include Charcot-Marie-Tooth disease type 1A (CMT1A), hereditary neuropathy with liability to pressure palsies (HNPP), Smith-Magenis syndrome (SMS), and mental retardation and congenital anomalies associated with partial duplication of 17p. We identified a patient with multifocal mononeuropathies and mild distal neuropathy, growth hormone deficiency, and mild mental retardation who was found to have a duplication of the SMS region of 17p11.2 and a deletion of the peripheral myelin protein 22 (PMP22) gene within 17p12 on the homologous chromosome. Further molecular analyses reveal that the dup(17)(p11.2p11.2) is a de novo event but that the PMP22 deletion is familial. The family members with deletions of PMP22 have abnormalities indicative of carpal tunnel syndrome, documented by electrophysiological studies prior to molecular analysis. The chromosomal duplication was shown by interphase FISH analysis to be a tandem duplication. These data indicate that familial entrapment neuropathies, such as carpal tunnel syndrome and focal ulnar neuropathy syndrome, can occur because of deletions of the PMP22 gene. The co-occurrence of the 17p11.2 duplication and the PMP22 deletion in this patient likely reflects the relatively high frequency at which these abnormalities arise and the underlying molecular characteristics of the genome in this region.
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PMID:DNA rearrangements on both homologues of chromosome 17 in a mildly delayed individual with a family history of autosomal dominant carpal tunnel syndrome. 997 84

Recombination between repeated sequences at various loci of the human genome are known to give rise to DNA rearrangements associated with many genetic disorders. Perhaps the most extensively characterized genomic region prone to rearrangement is 17p12, which is associated with the peripheral neuropathies, hereditary neuropathy with liability to pressure palsies (HNPP) and Charcot-Marie-Tooth disease type 1A (CMT1A;ref. 2). Homologous recombination between 24-kb flanking repeats, termed CMT1A-REPs, results in a 1.5-Mb deletion that is associated with HNPP, and the reciprocal duplication product is associated with CMT1A (ref. 2). Smith-Magenis syndrome (SMS) is a multiple congenital anomalies, mental retardation syndrome associated with a chromosome 17 microdeletion, del(17)(p11.2p11.2) (ref. 3,4). Most patients (>90%) carry deletions of the same genetic markers and define a common deletion. We report seven unrelated patients with de novo duplications of the same region deleted in SMS. A unique junction fragment, of the same apparent size, was identified in each patient by pulsed field gel electrophoresis (PFGE). Further molecular analyses suggest that the de novo17p11.2 duplication is preferentially paternal in origin, arises from unequal crossing over due to homologous recombination between flanking repeat gene clusters and probably represents the reciprocal recombination product of the SMS deletion. The clinical phenotype resulting from duplication [dup(17)(p11.2p11.2)] is milder than that associated with deficiency of this genomic region. This mechanism of reciprocal deletion and duplication via homologous recombination may not only pertain to the 17p11.2 region, but may also be common to other regions of the genome where interstitial microdeletion syndromes have been defined.
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PMID:Molecular mechanism for duplication 17p11.2- the homologous recombination reciprocal of the Smith-Magenis microdeletion. 1061 34

Charcot-Marie-Tooth disease (CMT), or hereditary motor and sensory neuropathy (HMSN), includes two main subtypes of CMT1/HMSN I (demyelinating), and CMT2/HMSN II (axonal). Further heterogeneity has been demonstrated by genetic molecular studies, with at least four responsible genes for CMT1. As for CMT2, a mutation in the neurofilament-light (NF-L) gene has been identified in a single family, and other CMT2 loci have been mapped. We propose a clinical classification of the CMT2 phenotypes, and review the features of the identified CMT2 genotypes. The following main subtypes of CMT2 are considered in the phenotype classification: classical CMT2, the variants of CMT2 showing atypical features that may represent either variance in the classical CMT2 phenotype or separate entities; CMT2 plus, i.e. complex forms with involvement of additional neural structures. The recognized CMT2 genotypes include: CMT2A (mapped to chromosome 1p35-36); CMT2B (3q13-22); CMT2C (with vocal cord paresis); CMT2D (7p14); CMT2E, related to a mutation in the NF-L gene on chromosome 8p21; proximal CMT2, or HMSN P (3q13.1); CMT2 with MPZ mutations; autosomal recessive CMT2 (1q21.2-q21.3); agenesis of the corpus callosum with sensorimotor neuronopathy (15q13-q15); CMT2 X-linked with deafness and mental retardation (Xq24-q26). The identified genotypes may correspond to previously described clinical subtypes of CMT2. In particular, classical CMT2 presents in association with NF-L gene mutation, in the only CMT2 family with known gene mutation, and in CMT2A patients. However, the features of classical CMT2 have been paradoxically reported also in families with MPZ mutation, and conversely several CMT2 families are not linked to the known CMT2 loci. Further cloning of the CMT2 genes will ultimately shed light on the pathogenic mechanism(s) implicated in the process of axonal degeneration, shared by the different CMT2 genotypes.
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PMID:Charcot-Marie-Tooth disease (CMT): distinctive phenotypic and genotypic features in CMT type 2. 1123 Oct 25

DNA copy number variation is an important cause of genetic disease. There are several techniques available to detect copy number changes of various sizes, each with their limitations in resolution and cost. Here we outline the development of multiplex amplifiable probe hybridization (MAPH) into a high-throughput diagnostic technique for detecting copy number variation of almost any size. Its application in testing for genetic mutations causing diseases, such as familial breast cancer, Charcot-Marie-Tooth disease Type 1A, Duchenne/Becker muscular dystrophy and familial colorectal cancer is described, as well as its use in identifying chromosomal changes in some individuals with mental retardation. The analysis of the data produced by MAPH is also considered, along with its potential for automation and development of microarray-based MAPH.
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PMID:DNA copy number analysis by MAPH: molecular diagnostic applications. 1213 2

Rab GTPases serve as master regulators of vesicular membrane transport on both the exo- and endocytic pathways. In their active forms, rab proteins serve in cargo selection and as scaffolds for the sequential assembly of effectors requisite for vesicle budding, cytoskeletal transport, and target membrane fusion. Rab protein function is in turn tightly regulated at the level of protein expression, localization, membrane association, and activation. Alterations in the rab GTPases and associated regulatory proteins or effectors have increasingly been implicated in causing human disease. Some diseases such as those resulting in bleeding and pigmentation disorders (Griscelli syndrome), mental retardation, neuropathy (Charcot-Marie-Tooth), kidney disease (tuberous sclerosis), and blindness (choroideremia) arise from direct loss of function mutations of rab GTPases or associated regulatory molecules. In contrast, in a number of cancers (prostate, liver, breast) as well as vascular, lung, and thyroid diseases, the overexpression of select rab GTPases have been tightly correlated with disease pathogenesis. Unique therapeutic opportunities lie ahead in developing strategies that target rab proteins and modulate the endocytic pathway.
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PMID:Rab proteins and endocytic trafficking: potential targets for therapeutic intervention. 1459 35

We report clinical findings and molecular cytogenetic analyses for two patients with translocations [t(14;17)(p12;p12) and t(15;17)(p12;p13.2)], in which the chromosome 17 breakpoints map at a large low-copy repeat (LCR) and a breakage-prone TRE-2 (USP6) oncogene, respectively. In family 1, a 6-year-old girl and her 5-year-old brother were diagnosed with mental retardation, short stature, dysmorphic features, and Charcot-Marie-Tooth disease type 1A (CMT1A). G-banding chromosome analysis showed a der(14)t(14;17)(p12;p12) in both siblings, inherited from their father, a carrier of the balanced translocation. Chromosome microarray and FISH analyses revealed that the PMP22 gene was duplicated. The chromosome 17 breakpoint was mapped within an approximately 383 kb LCR17pA that is known to also be the site of several breakpoints of different chromosome aberrations including the evolutionary translocation t(4;19) in Gorilla gorilla. In family two, a patient with developmental delay, subtle dysmorphic features, ventricular enlargement with decreased periventricular white matter, mild findings of bilateral perisylvian polymicrogyria and a very small anterior commissure, a cryptic duplication including the Miller-Dieker syndrome region was identified by chromosome microarray analysis. The chromosome 17 breakpoint was mapped by FISH at the TRE-2 oncogene. Both partner chromosome breakpoints were mapped on the short arm acrocentric heterochromatin within or distal to the rRNA cluster, distal to the region commonly rearranged in Robertsonian translocations. We propose that TRE-2 together with LCR17pA, located approximately 10 Mb apart, also generated the evolutionary gorilla translocation t(4;19). Our results support previous observations that the USP6 oncogene, LCRs, and repetitive DNA sequences play a significant role in the origin of constitutional chromosome aberrations and primate genome evolution.
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PMID:Evidence for involvement of TRE-2 (USP6) oncogene, low-copy repeat and acrocentric heterochromatin in two families with chromosomal translocations. 1679 15

The hereditary motor and sensory neuropathies (HMSNs, Charcot-Marie-Tooth neuropathies) are the most common degenerative disorders of the peripheral nervous system. In recent years a dramatic expansion has occurred in our understanding of the molecular basis and cell biology of the recessively inherited demyelinating and axonal neuropathies, with delineation of a number of new neuropathies. Mutations in some genes cause a wide variety of clinical, neurophysiologic, and pathologic phenotypes, rendering diagnosis difficult. The X-linked forms of HMSN represent at least 10%-15% of all HMSNs and have an expanded disease spectrum including demyelinating, intermediate, and axonal neuropathies, transient central nervous system (CNS) dysfunction, mental retardation, and hearing loss. This review presents an overview of the recessive and X-linked forms of HMSN observed in childhood, with particular reference to disease phenotype and neurophysiologic and pathologic abnormalities suggestive of specific diagnoses. These findings can be used by the clinician to formulate a differential diagnosis and guide targeted genetic testing.
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PMID:Autosomal-recessive and X-linked forms of hereditary motor and sensory neuropathy in childhood. 1741 May 79

Recent molecular cytogenetic data have shown that the constitution of complex chromosome rearrangements (CCRs) may be more complicated than previously thought. The complicated nature of these rearrangements challenges the accurate delineation of the chromosomal breakpoints and mechanisms involved. Here, we report a molecular cytogenetic analysis of two patients with congenital anomalies and unbalanced de novo CCRs involving chromosome 17p using high-resolution array-based comparative genomic hybridization (array CGH) and fluorescent in situ hybridization (FISH). In the first patient, a 4-month-old boy with developmental delay, hypotonia, growth retardation, coronal synostosis, mild hypertelorism, and bilateral club feet, we found a duplication of the Charcot-Marie-Tooth disease type 1A and Smith-Magenis syndrome (SMS) chromosome regions, inverted insertion of the Miller-Dieker lissencephaly syndrome region into the SMS region, and two microdeletions including a terminal deletion of 17p. The latter, together with a duplication of 21q22.3-qter detected by array CGH, are likely the unbalanced product of a translocation t(17;21)(p13.3;q22.3). In the second patient, an 8-year-old girl with mental retardation, short stature, microcephaly and mild dysmorphic features, we identified four submicroscopic interspersed 17p duplications. All 17 breakpoints were examined in detail by FISH analysis. We found that four of the breakpoints mapped within known low-copy repeats (LCRs), including LCR17pA, middle SMS-REP/LCR17pB block, and LCR17pC. Our findings suggest that the LCR burden in proximal 17p may have stimulated the formation of these CCRs and, thus, that genome architectural features such as LCRs may have been instrumental in the generation of these CCRs.
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PMID:Complex chromosome 17p rearrangements associated with low-copy repeats in two patients with congenital anomalies. 1745 15

In 2004, heterozygous mutations (N88S, S90L) in the Seipin/BSCL2 gene were identified in two autosomal dominant motor neuron diseases, distal hereditary motor neuropathy type V (OMIM #182960) and Silver syndrome (OMIM #270685). The Seipin/BSCL2 gene was originally identified as a candidate gene for congenital generalized lipodystrophy type 2 (CGL2) (OMIM #269700). Individuals with homozygous null mutations in seipin have severe lipoatrophy, insulin resistance, hypertriglyceridemia, and mental retardation without any abnormality of the motor neurons. Recent phenotype analyses of the N88S and S90L mutations have revealed a wide spectrum of Seipin/BSCL2-related motor neuron diseases, including Silver syndrome, distal hereditary motor neuropathy type V, variants of Charcot-Marie-Tooth disease type 2, and spastic paraplegia 17; therefore, these diseases should be termed "seipinopathies". Seipin is a transmembrane protein that is localized in the endoplasmic reticulum (ER). Interestingly, the N88S and S90L mutations both disturb the N-glycosylation motif, suggesting that improper glycosylation of seipin is closely associated with the pathogenesis of motor neuron diseases. Our recent study demonstrated that seipin is proteolytically cleaved into N and C-terminal fragments and then polyubiquitinated. The N88S and S90L mutations enhance ubiquitination and degradation by UPS, and N88S and S90L mutants appear to be improperly folded, resulting in their accumulation in the ER. Furthermore, expression of mutant seipin in cultured cells activates UPR stress and induces ER stress-mediated apoptosis. Our findings suggest that seipin-related motor neuron diseases, seipinopathies are novel conformational diseases, and we propose that the pathological process of these diseases is tightly associated with ER stress-mediated cell death.
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PMID:[Seipin/BSCL2-related motor neuron disease: Seipinopathy is a novel conformational disease associated with endoplasmic reticulum stress]. 1763 4

The Seipin/BSCL2 gene was originally identified as a loss-of-function gene for congenital generalized lipodystrophy type 2 (CGL2), a condition characterized by severe lipoatrophy, insulin resistance, hypertriglyceridaemia and mental retardation. Recently, gain-of-toxic-function mutations (namely, mutations N88S and S90L) in the seipin gene have been identified in autosomal dominant motor neuron diseases such as Silver syndrome/spastic paraplegia 17 (SPG17) (OMIM #270685) and distal hereditary motor neuropathy type V (dHMN-V) (OMIM #182960). Detailed phenotypic analyses have revealed that upper motor neurons, lower motor neurons and peripheral motor axons are variously affected in patients with these mutations. The clinical spectrum for these mutations is broad, encompassing Silver syndrome, some variants of Charcot-Marie-Tooth disease type 2, dHMNV and spastic paraplegia, even within a common pedigree. Therefore, we propose that seipin-related motor neuron diseases can be collectively referred to as 'seipinopathies'. Expression of the seipin protein can be detected in motor neurons in the spinal cord and white matter in the frontal lobe. This is consistent with the distribution of seipinopathies in the upper and lower motor neurons. Recent studies have shown that seipin, an endoplasmic reticulum (ER)-resident membrane protein, is an N-glycosylated protein that is proteolytically cleaved into N- and C-terminal fragments and is polyubiquitinated. Interestingly, the N88S and S90L mutations are in the N-glycosylation motif, and these mutations enhance ubiquitination and degradation of seipin by the ubiquitin-proteasome system (UPS). Furthermore, both mutations appear to result in proteins that are improperly folded, which leads to accumulation of the mutant protein in the ER. We have shown that expression of mutant forms of seipin in cultured cells activates the unfolded protein response (UPR) pathway and induces ER stress-mediated cell death. These findings suggest that seipinopathies are novel conformational diseases and that neurodegeneration in these diseases is tightly associated with ER stress, which has recently been reported to be associated with other neurodegenerative diseases. Further study of the pathological mechanisms of the mutant forms of seipin may lead to important new insights into motor neuron diseases, including other spastic paraplegia diseases and amyotrophic lateral sclerosis.
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PMID:Seipinopathy: a novel endoplasmic reticulum stress-associated disease. 1879 Aug 19


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