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• W2022111157 abstract "Menkes disease and occipital horn syndrome (OHS) are allelic, X-linked recessive copper-deficiency disorders resulting from mutations in ATP7A, or MNK. Classic Menkes disease has a severe phenotype, with death in early childhood, whereas OHS has a milder phenotype, with, mainly, connective-tissue abnormalities. Data suggest that steady-state localization of ATP7A to the trans-Golgi network (TGN) is necessary for proper activity of lysyl oxidase, which is the predominant cuproenzyme whose activity is deficient in OHS and which is essential for maintenance of connective-tissue integrity. Recently, it was reported that ATP7A-transcript levels as low as 2%–5% of normal are sufficient to result in the milder phenotype, OHS, rather than the phenotype of Menkes disease. In contrast to previously reported cases of OHS, we describe a case of OHS in which, because of a frameshift mutation, no normal ATP7A is produced. Although abundant levels of mutant transcript are present, there are substantially reduced levels of the truncated protein, which lacks the key dileucine motif L1487L1488. It has been demonstrated that the dileucine motif L1487L1488 functions as an endocytic signal for ATP7A cycling between the TGN and the plasma membrane. The present report is the first to describe an ATP7A truncation that results in OHS rather than in Menkes disease. The data from the present report support the concepts that (1) OHS results from lower levels of functional ATP7A and (2) ATP7A does not require the dileucine motif to function in copper efflux. Menkes disease and occipital horn syndrome (OHS) are allelic, X-linked recessive copper-deficiency disorders resulting from mutations in ATP7A, or MNK. Classic Menkes disease has a severe phenotype, with death in early childhood, whereas OHS has a milder phenotype, with, mainly, connective-tissue abnormalities. Data suggest that steady-state localization of ATP7A to the trans-Golgi network (TGN) is necessary for proper activity of lysyl oxidase, which is the predominant cuproenzyme whose activity is deficient in OHS and which is essential for maintenance of connective-tissue integrity. Recently, it was reported that ATP7A-transcript levels as low as 2%–5% of normal are sufficient to result in the milder phenotype, OHS, rather than the phenotype of Menkes disease. In contrast to previously reported cases of OHS, we describe a case of OHS in which, because of a frameshift mutation, no normal ATP7A is produced. Although abundant levels of mutant transcript are present, there are substantially reduced levels of the truncated protein, which lacks the key dileucine motif L1487L1488. It has been demonstrated that the dileucine motif L1487L1488 functions as an endocytic signal for ATP7A cycling between the TGN and the plasma membrane. The present report is the first to describe an ATP7A truncation that results in OHS rather than in Menkes disease. The data from the present report support the concepts that (1) OHS results from lower levels of functional ATP7A and (2) ATP7A does not require the dileucine motif to function in copper efflux. Menkes disease (MIM 309400) and occipital horn syndrome (OHS [MIM 304150]) are allelic, X-linked recessive copper-deficiency disorders (Levinson et al. Levinson et al., 1993Levinson B Gitschier J Vulpe C Whitney S Yang S Packman S Are X-linked cutis laxa and Menkes disease allelic?.Nat Genet. 1993; 3: 6Crossref PubMed Scopus (33) Google Scholar; Das et al. Das et al., 1995Das S Levinson B Vulpe C Whitney S Gitschier J Packman S Similar splicing mutations of the Menkes/mottled copper-transporting ATPase gene in occipital horn syndrome and the blotchy mouse.Am J Hum Genet. 1995; 56: 570-576PubMed Google Scholar) resulting from mutations in ATP7A, or MNK (GenBank accession number NM_000052) (Chelly et al. Chelly et al., 1993Chelly J Tümer Z Tonnesen T Petterson A Ishikawa-Brush Y Tommerup N Horn N Monaco AP Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein.Nat Genet. 1993; 3: 14-19Crossref PubMed Scopus (605) Google Scholar; Mercer et al. Mercer et al., 1993Mercer JFB Livingston J Hall B Paynter JA Begy C Chandrasekharappa S Lockhart P Grimes A Bhave M Siemieniak D Glover TW Isolation of a partial candidate gene for Menkes disease by positional cloning.Nat Genet. 1993; 3: 20-25Crossref PubMed Scopus (606) Google Scholar; Vulpe et al. Vulpe et al., 1993Vulpe C Levinson B Whitney S Packman S Gitschier J Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase.Nat Genet. 1993; 3: 7-13Crossref PubMed Scopus (1175) Google Scholar). ATP7A contains 23 exons that span a genomic region of ∼140 kb (Dierick et al. Dierick et al., 1995Dierick HA Ambrosini L Spencer J Glover TW Mercer JFB Molecular structure of the Menkes disease gene (ATP7A).Genomics. 1995; 28: 462-469Crossref PubMed Scopus (69) Google Scholar; Tümer et al. Tümer et al., 1995Tümer Z Vural B Tonnesen T Chelly J Monaco AP Horn N Characterization of the exon structure of the Menkes disease gene using vectorette PCR.Genomics. 1995; 26: 437-442Crossref PubMed Scopus (80) Google Scholar) and has a predominant transcription product of ∼8.5 kb (Chelly et al. Chelly et al., 1993Chelly J Tümer Z Tonnesen T Petterson A Ishikawa-Brush Y Tommerup N Horn N Monaco AP Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein.Nat Genet. 1993; 3: 14-19Crossref PubMed Scopus (605) Google Scholar; Mercer et al. Mercer et al., 1993Mercer JFB Livingston J Hall B Paynter JA Begy C Chandrasekharappa S Lockhart P Grimes A Bhave M Siemieniak D Glover TW Isolation of a partial candidate gene for Menkes disease by positional cloning.Nat Genet. 1993; 3: 20-25Crossref PubMed Scopus (606) Google Scholar; Vulpe et al. Vulpe et al., 1993Vulpe C Levinson B Whitney S Packman S Gitschier J Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase.Nat Genet. 1993; 3: 7-13Crossref PubMed Scopus (1175) Google Scholar). ATP7A is ∼170 kD in size and is a member of the P-type–ATPase family (Chelly et al. Chelly et al., 1993Chelly J Tümer Z Tonnesen T Petterson A Ishikawa-Brush Y Tommerup N Horn N Monaco AP Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein.Nat Genet. 1993; 3: 14-19Crossref PubMed Scopus (605) Google Scholar; Mercer et al. Mercer et al., 1993Mercer JFB Livingston J Hall B Paynter JA Begy C Chandrasekharappa S Lockhart P Grimes A Bhave M Siemieniak D Glover TW Isolation of a partial candidate gene for Menkes disease by positional cloning.Nat Genet. 1993; 3: 20-25Crossref PubMed Scopus (606) Google Scholar; Vulpe et al. Vulpe et al., 1993Vulpe C Levinson B Whitney S Packman S Gitschier J Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase.Nat Genet. 1993; 3: 7-13Crossref PubMed Scopus (1175) Google Scholar). P-type ATPases transport cations across cellular membranes by using energy generated by ATP hydrolysis (Pedersen et al. Pedersen and Carafoli, 1987Pedersen PL Carafoli E Ion motive ATPases. I. Ubiquity, properties, and significance to cell function.Trends Biochem Sci. 1987; 12: 146-150Abstract Full Text PDF Scopus (808) Google Scholar). ATP7A functions (a) to transport copper from the gastrointestinal tract into the bloodstream, (b) to efflux excess copper from the cell, and (c) for intracellular delivery, within the secretory pathway, of copper to cuproenzymes (for reviews, see Kaler Kaler, 1998Kaler SG Metabolic and molecular bases of Menkes disease and occipital horn syndrome.Pediatr Dev Pathol. 1998; 1: 85-98Crossref PubMed Scopus (90) Google Scholar; Camakaris et al. Camakaris et al., 1999Camakaris J Voskoboinik I Mercer JF Molecular mechanism of copper homeostasis.Biochem Biophys Res Commun. 1999; 261: 225-232Crossref PubMed Scopus (194) Google Scholar; Harris Harris, 2000Harris ED Cellular copper transport and metabolism.Annu Rev Nutr. 2000; 20: 291-310Crossref PubMed Scopus (207) Google Scholar). At basal intracellular copper levels, the steady-state localization of ATP7A is to the trans-Golgi Network (TGN) (Petris et al. Petris et al., 1996Petris MJ Mercer JF Culvenor JG Lockhart P Gleeson PA Camakaris J Ligand- regulated transport of the Menkes copper P-type ATPase efflux pump from the Golgi apparatus to the plasma membrane: a novel mechanism of regulated trafficking.EMBO J. 1996; 15: 6084-6095Crossref PubMed Scopus (515) Google Scholar; Yamaguchi et al. Yamaguchi et al., 1996Yamaguchi Y Heiny ME Suzuki M Gitlin JD Biochemical characterization and intracellular localization of the Menkes disease protein.Proc Natl Acad Sci USA. 1996; 93: 14030-14035Crossref PubMed Scopus (182) Google Scholar; Dierick et al. Dierick et al., 1997Dierick HA Adam AN Escara-Wilke JF Glover TW Immunocytochemical localization of the Menkes copper transport protein (ATP7A) to the trans-Golgi network.Hum Mol Genet. 1997; 6: 409-416Crossref PubMed Scopus (95) Google Scholar). However, in an environment with excess copper, ATP7A is transported, via secretory vesicles, to the plasma membrane, where it functions to efflux copper from the cell (Petris et al. Petris et al., 1996Petris MJ Mercer JF Culvenor JG Lockhart P Gleeson PA Camakaris J Ligand- regulated transport of the Menkes copper P-type ATPase efflux pump from the Golgi apparatus to the plasma membrane: a novel mechanism of regulated trafficking.EMBO J. 1996; 15: 6084-6095Crossref PubMed Scopus (515) Google Scholar, Petris and Mercer, 1999Petris MJ Mercer JFB The Menkes protein (ATP7A; MNK) cycles via the plasma membrane both in basal and elevated extracellular copper using a C-terminal di-leucine endocytic signal.Hum Mol Genet. 1999; 8: 2107-2115Crossref PubMed Scopus (136) Google Scholar; La Fontaine et al. La Fontaine et al., 1998La Fontaine S Firth SD Lockhart PJ Brooks H Parton RG Camakaris J Mercer JFB Functional analysis and intracellular localization of the human Menkes protein (MNK) stably expressed from a cDNA construct in Chinese hamster ovary cells (CHO-K1).Hum Mol Genet. 1998; 7: 1293-1300Crossref PubMed Scopus (77) Google Scholar). In response to intracellular copper levels, it is believed that ATP7A cycles between the TGN and the plasma membrane. The dileucine motif L1487L1488 functions as an endocytic signal for ATP7A cycling (Petris et al. Petris et al., 1998Petris MJ Camakaris J Greenough M LaFontaine S Mercer JFB A C-terminal di- leucine is required for localization of the Menkes protein in the trans-Golgi network.Hum Mol Genet. 1998; 7: 2063-2071Crossref PubMed Scopus (132) Google Scholar, Petris and Mercer, 1999Petris MJ Mercer JFB The Menkes protein (ATP7A; MNK) cycles via the plasma membrane both in basal and elevated extracellular copper using a C-terminal di-leucine endocytic signal.Hum Mol Genet. 1999; 8: 2107-2115Crossref PubMed Scopus (136) Google Scholar; Francis et al. Francis et al., 1999Francis MJ Jones EE Levy ER Martin RL Ponnambalam S Monaco AP Identification of a di-leucine motif within the C terminus domain of the Menkes disease protein that mediates endocytosis from the plasma membrane.J Cell Sci. 1999; 112: 1721-1732Crossref PubMed Google Scholar) and is necessary for internalization of the protein from the plasma membrane (Francis et al. Francis et al., 1999Francis MJ Jones EE Levy ER Martin RL Ponnambalam S Monaco AP Identification of a di-leucine motif within the C terminus domain of the Menkes disease protein that mediates endocytosis from the plasma membrane.J Cell Sci. 1999; 112: 1721-1732Crossref PubMed Google Scholar). However, data from Petris et al. (Petris et al., 1998Petris MJ Camakaris J Greenough M LaFontaine S Mercer JFB A C-terminal di- leucine is required for localization of the Menkes protein in the trans-Golgi network.Hum Mol Genet. 1998; 7: 2063-2071Crossref PubMed Scopus (132) Google Scholar) suggest that the dileucine motif L1487L1488 is not necessary for ATP7A to function in copper efflux. Classic Menkes disease is a rare multisystem disorder with a severe phenotype including neonatal neurological degeneration, hypopigmentation, skin and joint laxity, coarse and twisted hair (pili torti), hypothermia, seizures, failure to thrive, and death typically by the age of 3 years (Menkes et al. Menkes et al., 1962Menkes JHM Alter M Steigleder GK Weakley DR Sung JH A sex-linked recessive disorder with retardation of growth, peculiar hair and focal cerebral and cerebellar degeneration.Pediatrics. 1962; 29: 764-779PubMed Google Scholar). In patients with Menkes disease, abnormal, or nonfunctional, ATP7A results in decreased intestinal absorption of copper, which leads to decreased copper in the plasma, liver, and brain (for review, see Kaler Kaler, 1998Kaler SG Metabolic and molecular bases of Menkes disease and occipital horn syndrome.Pediatr Dev Pathol. 1998; 1: 85-98Crossref PubMed Scopus (90) Google Scholar). The clinical phenotype of Menkes disease can be attributed to the reduced activity of several cuproenzymes, such as lysyl oxidase, tyrosinase, copper/zinc superoxide dismutase, dopamine β-hydroxylase, and cytochrome c oxidase (Menkes Menkes, 1988Menkes JH Kinky hair disease: twenty five years later.Brain Dev. 1988; 10: 77-79Abstract Full Text PDF PubMed Scopus (69) Google Scholar). In addition, it has been demonstrated that there is an accumulation of copper in certain tissues and cell types, which indicates that ATP7A in these patients is not functioning properly to efflux copper from the cell (for review, see Kaler Kaler, 1998Kaler SG Metabolic and molecular bases of Menkes disease and occipital horn syndrome.Pediatr Dev Pathol. 1998; 1: 85-98Crossref PubMed Scopus (90) Google Scholar). Thus, at the tissue level, Menkes disease can be considered a disorder of copper maldistribution. OHS, formerly known as “X-linked cutis laxa” or “Ehlers-Danlos syndrome type 9,” has a phenotype milder than that of Menkes disease, mainly composed of connective-tissue manifestations, including skin laxity, hyperextensible joints, bladder diverticula, characteristic occipital exostoses, and, occasionally, mild neurological involvement (Lazoff et al. Lazoff et al., 1975Lazoff SF Rybak JJ Parker BR Luzzatti L Skeletal dysplasia, occipital horns, diarrhea and obstructive uropathy—a new hereditary syndrome.Birth Defects Orig Artic Ser. 1975; 11: 71-74PubMed Google Scholar; Byers et al. Byers et al., 1980Byers PH Siegel RC Holbrook KA Narayanan AS Bornstein P Hall JG X-linked cutis laxa due to deficiency of lysyl oxidase.N Engl J Med. 1980; 303: 61-65Crossref PubMed Scopus (145) Google Scholar; for review, see Tsukahara et al. Tsukahara et al., 1994Tsukahara M Imaizumi K Kawai S Kajii T Occipital horn syndrome: report of a patient and review of the literature.Clin Genet. 1994; 45: 32-35Crossref PubMed Scopus (38) Google Scholar). Byers et al. (Byers et al., 1980Byers PH Siegel RC Holbrook KA Narayanan AS Bornstein P Hall JG X-linked cutis laxa due to deficiency of lysyl oxidase.N Engl J Med. 1980; 303: 61-65Crossref PubMed Scopus (145) Google Scholar) demonstrated that patients with OHS have decreased activity of the cuproenzyme lysyl oxidase, which functions in the initiation of cross-linking of both collagen and elastin. It has been hypothesized that OHS results from the presence of low levels of functional ATP7A, unlike Menkes disease, in which no normal ATP7A activity exists (Das et al. Das et al., 1995Das S Levinson B Vulpe C Whitney S Gitschier J Packman S Similar splicing mutations of the Menkes/mottled copper-transporting ATPase gene in occipital horn syndrome and the blotchy mouse.Am J Hum Genet. 1995; 56: 570-576PubMed Google Scholar). This hypothesis has been supported by a recent study that demonstrates that ATP7A-transcript levels as low as 2%–5% of normal are sufficient to result in the milder phenotype, OHS, as opposed to Menkes disease (Møller et al. Møller et al., 2000Møller LB Tümer Z Lund C Petersen C Cole T Hanusch R Seidel J Jensen LR Horn N Similar splice-site mutations of the ATP7A gene lead to different phenotypes: classical Menkes disease or occipital horn syndrome.Am J Hum Genet. 2000; 66: 1211-1220Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar). It has been postulated that lysyl oxidase is more sensitive than other cuproenzymes to copper deficiency, thus resulting in decreased lysyl oxidase activity in patients with OHS (Das et al. Das et al., 1995Das S Levinson B Vulpe C Whitney S Gitschier J Packman S Similar splicing mutations of the Menkes/mottled copper-transporting ATPase gene in occipital horn syndrome and the blotchy mouse.Am J Hum Genet. 1995; 56: 570-576PubMed Google Scholar; Levinson et al. Levinson et al., 1996Levinson B Conant R Schnur R Das S Packman S Gitschier J A repeated element in the regulatory region of the MNK gene and its deletion in a patient with occipital horn syndrome.Hum Mol Genet. 1996; 5: 1737-1742Crossref PubMed Scopus (40) Google Scholar). There are 35–40 known cases of OHS worldwide (Møller et al. Møller et al., 2000Møller LB Tümer Z Lund C Petersen C Cole T Hanusch R Seidel J Jensen LR Horn N Similar splice-site mutations of the ATP7A gene lead to different phenotypes: classical Menkes disease or occipital horn syndrome.Am J Hum Genet. 2000; 66: 1211-1220Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar), but mutations in only 8 cases have been elucidated at the molecular level (table 1). In seven of these eight cases, the mutation leads to aberrant splicing of the ATP7A transcript (Kaler et al. Kaler et al., 1994Kaler SG Gallo LK Proud VK Percy AK Mark Y Segal NA Goldstein DS Holmes CS Gahl WA Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locus.Nat Genet. 1994; 8: 195-202Crossref PubMed Scopus (196) Google Scholar; Das et al. Das et al., 1995Das S Levinson B Vulpe C Whitney S Gitschier J Packman S Similar splicing mutations of the Menkes/mottled copper-transporting ATPase gene in occipital horn syndrome and the blotchy mouse.Am J Hum Genet. 1995; 56: 570-576PubMed Google Scholar; Ronce et al. Ronce et al., 1997Ronce N Moizard MP Robb L Toutain A Villard L Moraine C A C2055T transition in exon 8 of the ATP7A gene is associated with exon skipping in an occipital horn syndrome family.Am J Hum Genet. 1997; 61: 233-238Abstract Full Text PDF PubMed Google Scholar; Qi and Byers Qi and Byers, 1998Qi M Byers PH Constitutive skipping of alternatively spliced exon 10 in the ATP7A gene abolishes Golgi localization of the Menkes protein and produces the occipital horn syndrome.Hum Mol Genet. 1998; 7: 465-469Crossref PubMed Scopus (60) Google Scholar; Møller et al. Møller et al., 2000Møller LB Tümer Z Lund C Petersen C Cole T Hanusch R Seidel J Jensen LR Horn N Similar splice-site mutations of the ATP7A gene lead to different phenotypes: classical Menkes disease or occipital horn syndrome.Am J Hum Genet. 2000; 66: 1211-1220Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar; Gu et al. Gu et al., 2001Gu YH Kodam H Murata Y Mochizuki D Yanagawa Y Ushijima H Shiba T Lee CC ATP7A gene mutations in 16 patients with Menkes disease and a patient with occipital horn syndrome.Am J Med Genet. 2001; 99: 217-222Crossref PubMed Scopus (68) Google Scholar). In four of the cases of OHS with a splice mutation, low levels of normal transcript have been detected (Levinson et al. Levinson et al., 1993Levinson B Gitschier J Vulpe C Whitney S Yang S Packman S Are X-linked cutis laxa and Menkes disease allelic?.Nat Genet. 1993; 3: 6Crossref PubMed Scopus (33) Google Scholar; Das et al. Das et al., 1995Das S Levinson B Vulpe C Whitney S Gitschier J Packman S Similar splicing mutations of the Menkes/mottled copper-transporting ATPase gene in occipital horn syndrome and the blotchy mouse.Am J Hum Genet. 1995; 56: 570-576PubMed Google Scholar; Møller et al. Møller et al., 2000Møller LB Tümer Z Lund C Petersen C Cole T Hanusch R Seidel J Jensen LR Horn N Similar splice-site mutations of the ATP7A gene lead to different phenotypes: classical Menkes disease or occipital horn syndrome.Am J Hum Genet. 2000; 66: 1211-1220Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar; Gu et al. Gu et al., 2001Gu YH Kodam H Murata Y Mochizuki D Yanagawa Y Ushijima H Shiba T Lee CC ATP7A gene mutations in 16 patients with Menkes disease and a patient with occipital horn syndrome.Am J Med Genet. 2001; 99: 217-222Crossref PubMed Scopus (68) Google Scholar). Missense mutations in two reported cases of OHS resulted in aberrant splicing of the transcript with an amino acid change in the normal transcript, which did not adversely affect the function of ATP7A (Kaler et al. Kaler et al., 1994Kaler SG Gallo LK Proud VK Percy AK Mark Y Segal NA Goldstein DS Holmes CS Gahl WA Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locus.Nat Genet. 1994; 8: 195-202Crossref PubMed Scopus (196) Google Scholar; Ronce et al. Ronce et al., 1997Ronce N Moizard MP Robb L Toutain A Villard L Moraine C A C2055T transition in exon 8 of the ATP7A gene is associated with exon skipping in an occipital horn syndrome family.Am J Hum Genet. 1997; 61: 233-238Abstract Full Text PDF PubMed Google Scholar). Qi and Byers (Qi and Byers, 1998Qi M Byers PH Constitutive skipping of alternatively spliced exon 10 in the ATP7A gene abolishes Golgi localization of the Menkes protein and produces the occipital horn syndrome.Hum Mol Genet. 1998; 7: 465-469Crossref PubMed Scopus (60) Google Scholar) did not detect normal ATP7A transcript by reverse-transcription PCR (RT-PCR) in a family with OHS with a splice mutation in intron 10. However, it is possible that the affected members of that family could produce a low level of normal ATP7A, similar to that produced in affected members of a family described by Møller et al. (Møller et al., 2000Møller LB Tümer Z Lund C Petersen C Cole T Hanusch R Seidel J Jensen LR Horn N Similar splice-site mutations of the ATP7A gene lead to different phenotypes: classical Menkes disease or occipital horn syndrome.Am J Hum Genet. 2000; 66: 1211-1220Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar). In addition, Levinson et al. (Levinson et al., 1996Levinson B Conant R Schnur R Das S Packman S Gitschier J A repeated element in the regulatory region of the MNK gene and its deletion in a patient with occipital horn syndrome.Hum Mol Genet. 1996; 5: 1737-1742Crossref PubMed Scopus (40) Google Scholar) described a patient with OHS who did not have a mutation in the coding region of ATP7A but, instead, had a 98-bp deletion in the regulatory region of ATP7A. Northern analysis indicated normal transcript levels; however, a chloramphenicol acetyltransferase (CAT) reporter assay suggested that the promoter deletion would result in decreased expression of ATP7A.Table 1Summary of OHS MutationsMutationaIVS = intervening sequence.Splice Mutation?Splice SitemRNASource(s)−403del98ntNo…Deletion in regulatory region, normal transcript level, reduced CAT activityLevinson et al. (Levinson et al., 1996Levinson B Conant R Schnur R Das S Packman S Gitschier J A repeated element in the regulatory region of the MNK gene and its deletion in a patient with occipital horn syndrome.Hum Mol Genet. 1996; 5: 1737-1742Crossref PubMed Scopus (40) Google Scholar)IVS6+2del(taag)YesDonorExon 6 skipped→frameshift→PTC, reduced normal transcript levelMøller et al. (Møller et al., 2000Møller LB Tümer Z Lund C Petersen C Cole T Hanusch R Seidel J Jensen LR Horn N Similar splice-site mutations of the ATP7A gene lead to different phenotypes: classical Menkes disease or occipital horn syndrome.Am J Hum Genet. 2000; 66: 1211-1220Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar), Gu et al. (Gu et al., 2001Gu YH Kodam H Murata Y Mochizuki D Yanagawa Y Ushijima H Shiba T Lee CC ATP7A gene mutations in 16 patients with Menkes disease and a patient with occipital horn syndrome.Am J Med Genet. 2001; 99: 217-222Crossref PubMed Scopus (68) Google Scholar)2055C→TYes…Exon 8 skipped→frameshift→PTC, exons 8–10 skipped, reduced transcript level with S637LRonce et al. (Ronce et al., 1997Ronce N Moizard MP Robb L Toutain A Villard L Moraine C A C2055T transition in exon 8 of the ATP7A gene is associated with exon skipping in an occipital horn syndrome family.Am J Hum Genet. 1997; 61: 233-238Abstract Full Text PDF PubMed Google Scholar)IVS10+3a→tYesDonorExon 10 skipped→in-frame deletion→deletion of transmembrane domains 3 and 4 in protein, abundant abnormal transcript levelQi and Byers (Qi and Byers, 1998Qi M Byers PH Constitutive skipping of alternatively spliced exon 10 in the ATP7A gene abolishes Golgi localization of the Menkes protein and produces the occipital horn syndrome.Hum Mol Genet. 1998; 7: 465-469Crossref PubMed Scopus (60) Google Scholar)2642A→GYesDonorExon 11 skipped→frameshift→PTC, exons 11 and 12 skipped→frame-shift→PTC, reduced transcript level with S833GKaler et al. (Kaler et al., 1994Kaler SG Gallo LK Proud VK Percy AK Mark Y Segal NA Goldstein DS Holmes CS Gahl WA Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locus.Nat Genet. 1994; 8: 195-202Crossref PubMed Scopus (196) Google Scholar)IVS14−4a→gYesAcceptorExon 15 skipped→in-frame deletion→deletion of transduction domain, abundant abnormal transcript level, reduced normal transcript levelDas et al. (Das et al., 1995Das S Levinson B Vulpe C Whitney S Gitschier J Packman S Similar splicing mutations of the Menkes/mottled copper-transporting ATPase gene in occipital horn syndrome and the blotchy mouse.Am J Hum Genet. 1995; 56: 570-576PubMed Google Scholar)IVS17+5g→aYesDonorExon 17 skipped→frameshift→PTC, reduced normal transcript levelDas et al. (Das et al., 1995Das S Levinson B Vulpe C Whitney S Gitschier J Packman S Similar splicing mutations of the Menkes/mottled copper-transporting ATPase gene in occipital horn syndrome and the blotchy mouse.Am J Hum Genet. 1995; 56: 570-576PubMed Google Scholar), Levinson et al. (Levinson et al., 1993Levinson B Gitschier J Vulpe C Whitney S Yang S Packman S Are X-linked cutis laxa and Menkes disease allelic?.Nat Genet. 1993; 3: 6Crossref PubMed Scopus (33) Google Scholar)4497–4499delGNo…Frameshift→PTC, abundant abnormal transcript levelPresent studya IVS = intervening sequence. Open table in a new tab In the present report, we describe a frameshift mutation in a family with classic OHS. The mutation is novel—that is, it does not result in aberrant splicing of the transcript, as has been seen in seven of the eight previously reported mutations. In our case, no normal ATP7A mRNA is transcribed, owing to a frameshift mutation at codon 1451, which leads to premature truncation of the predicted protein. Because the protein was truncated prior to L14871488 in the carboxy terminus, it provides insight as to the importance, with respect to phenotype, of this signal. The pedigree of this family with classic OHS reveals a pattern of affected individuals that is consistent with X-linked inheritance (fig. 1). The proband (III-2) sat without assistance at the age of 7 mo and was able to crawl at the age of 7.5 mo. On examination, he exhibited multiple bladder diverticula, renal calculus, vesicoureteral reflux, bilateral inguinal hernia repair, neurogenic bladder, genu valgum, and pectus excavatum; he also had mildly hyperelastic skin, especially over the abdomen, and required special education. He did not exhibit chronic diarrhea, orthostatic hypotension, or dysautonomic symptoms. A skeletal survey of this individual revealed bilateral occipital horns, mild lower-thoracic and lumbar platyspondyly, marked pectus excavatum, broad scapular necks, clavicular handlebar/hammer contour, humeral and femoral diaphyseal wavy contour, bulbous ulnar-coronoid and radial bowing of the forearms, rounded iliac-wing contour with broadening in the medial/lateral dimension, bilateral coxa valga, and minimal dextroconvex scoliosis from T4 to L4. At the age of 8 years, III-2's serum copper level was slightly low, at 60 μg/dl (normal range 70–150 μg/dl), as was the serum ceruloplasmin level, which was 18.9 mg/dl (normal range 20–42 mg/dl). At the age of 10 years 9 mo, he was given the Woodcock-Johnson Tests of Cognitive Ability, the Woodcock-Johnson Tests of Achievement, the Wechsler Individual Achievement Test, the Bender Gestalt Test, and the Human Figure Drawing Task. For the Wechsler Individual Achievement Test, he had scores that were age equivalent to 8 years 3 mo in basic reading, 8 years in math reasoning, and 8 years 6 mo in spelling. He had a standard score of 84 for the Woodcock-Johnson Tests of Cognitive Ability, which is in the low-average range. III-2's affected brother (III-3), maternal uncle (II-10), and cousin (II-5) were similarly affected but with slight variability in severity. The pattern of inheritance and the clinical findings were consistent with a diagnosis of OHS. After obtaining informed consent, we collected skin biopsies and blood samples from III-2, III-3, III-2's unaffected brother (III-1), and their carrier mother (II-6), in accordance with the procedures of the institutional review boards of the University of Michigan Medical School. Fibroblast and Epstein-Barr virus–transformed lymphoblastoid cell lines were generated and cultured according to standard procedures. To determine whether, in our case, the mutation involved a splice site, we performed RT-PCR. PCR products were generated using cDNA reverse transcribed from total RNA (SuperscriptII Reverse Transcriptase; GibcoBRL) and eight primer pairs that spanned the coding region of ATP7A. No novel aberrant splicing was detected by RT-PCR (not shown), suggesting that in both III-2 an" @default.
• W2022111157 created "2016-06-24" @default.
• W2022111157 creator A5002683233 @default.
• W2022111157 creator A5017732426 @default.
• W2022111157 creator A5024769625 @default.
• W2022111157 creator A5070758221 @default.
• W2022111157 date "2001-08-01" @default.
• W2022111157 modified "2023-10-03" @default.
• W2022111157 title "A Novel Frameshift Mutation in Exon 23 of ATP7A (MNK) Results in Occipital Horn Syndrome and Not in Menkes Disease" @default.
• W2022111157 cites W117293620 @default.
• W2022111157 cites W1484470448 @default.
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