HGNC Approved Gene Symbol: ATP7A
SNOMEDCT: 59178007, 59399004, 766764008;
Cytogenetic location: Xq21.1 Genomic coordinates (GRCh38): X:77,910,693-78,050,395 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq21.1 | Menkes disease | 309400 | X-linked recessive | 3 |
| Neuronopathy, distal hereditary motor, X-linked | 300489 | X-linked recessive | 3 | |
| Occipital horn syndrome | 304150 | X-linked recessive | 3 |
The ATP7A gene encodes a transmembrane copper-transporting P-type ATPase (summary by Vulpe et al., 1993).
The ATP7A gene was cloned as a candidate for the site of mutations causing Menkes disease (MNK; 309400) by 3 independent groups (Vulpe et al., 1993; Chelly et al., 1993; Mercer et al., 1993). By a database search of the predicted sequence, Vulpe et al. (1993) found strong homology to P-type ATPases, a family of integral membrane proteins that use an aspartylphosphate intermediate to transport cations across membranes. The 1,500-residue protein was found to have the characteristics of a copper-binding protein. It has 6 N-terminal copper binding sites and a catalytic transduction core with several functional domains. Northern blot analysis showed that the mRNA of the gene, which was symbolized 'MNK' before its precise nature was known, is present in a variety of cell types and tissues, except liver, in which expression is reduced or absent. The findings were consistent with the clinical observation that the liver is largely unaffected in Menkes disease and fails to accumulate excess copper.
Levinson et al. (1994) and Mercer et al. (1994) isolated the mouse homolog of the Menkes disease gene. The mouse protein shows 89% identity to the human protein, and both proteins contain 8 transmembrane domains.
Tumer et al. (1995) determined that the ATP7A gene spans about 150 kb of genomic DNA and contains 23 exons. The ATG start codon is in the second exon. The ATP7A and ATP7B (606882) genes showed strikingly similar exonic structures, with almost identical structures starting from the fifth metal-binding domain, suggesting the presence of a common ancestor encoding 1, and possibly 2, metal-binding domains in addition to the ATPase 'core.'
Dierick et al. (1995) showed that the ATP7A gene contains 23 exons distributed over approximately 140 kb of genomic DNA. The authors showed that exon 10 is alternatively spliced. They found that the structures of the ATP7A and ATP7B genes are similar in the 3-prime two-thirds region, consistent with their common evolutionary ancestry.
Kuo et al. (1997) determined the gene expression patterns during mouse embryonic development for the Atp7a and Atp7b genes by RNA in situ hybridization. Atp7a expression was widespread throughout development whereas Atp7b expression was more delimited. Kuo et al. (1997) suggested that Atp7a functions primarily in the homeostatic maintenance of cell copper levels, whereas Atp7b may be involved specifically in the biosynthesis of distinct cuproproteins in different tissues.
Studies in cultured cells localized the MNK protein to the final compartment of the Golgi apparatus, the trans-Golgi network (TGN). At this location, MNK is predicted to supply copper to the copper-dependent enzymes as they migrate through the secretory pathway. However, under conditions of elevated extracellular copper, the MNK protein undergoes a rapid relocalization to the plasma membrane where it functions in the efflux of copper from cells. By in vitro mutagenesis of the human ATP7A cDNA and immunofluorescence detection of mutant forms of the MNK protein expressed in cultured cells, Petris et al. (1998) demonstrated that the dileucine, L1487L1488, was essential for localization of MNK within the TGN, but not for copper efflux. They suggested that this dileucine motif is a putative endocytic targeting motif necessary for the retrieval of MNK from the plasma membrane to the TGN. Qian et al. (1998) and Francis et al. (1998) demonstrated that the third transmembrane region of the MNK protein functions as a TGN targeting signal; Petris et al. (1998) suggested that MNK localization to the TGN may be a 2-step process involving TGN retention by the transmembrane region, and recycling to this compartment from the plasma membrane via the L1487L1488 motif.
Petris et al. (2000) investigated whether the ATP7A protein is required for the activity of tyrosinase (606933), a copper-dependent enzyme involved in melanogenesis that is synthesized within the secretory pathway. Recombinant tyrosinase expressed in immortalized Menkes fibroblast cell lines was inactive, whereas in normal fibroblasts known to express ATP7A there was substantial tyrosinase activity. Coexpression of ATP7A and tyrosinase from plasmid constructs in Menkes fibroblasts led to the activation of tyrosinase and melanogenesis. This ATP7A-dependent activation of tyrosinase was impaired by the chelation of copper in the medium of cells and after mutation of the invariant phosphorylation site at aspartic acid residue 1044 of ATP7A. The authors proposed that ATP7A transports copper into the secretory pathway of mammalian cells to activate copper-dependent enzymes.
Cobbold et al. (2002) showed that endogenous ATP7A in cultured cell lines was localized to the distal Golgi apparatus and translocated to the plasma membrane in response to exogenous copper ions. This transport event was not blocked by expression of a dominant-negative mutant protein kinase D (PRKCM; 605435), an enzyme implicated in regulating constitutive trafficking from the TGN to the plasma membrane, whereas constitutive transport of CD4 (186940) was inhibited. In contrast, protein kinase A inhibitors blocked copper-stimulated ATP7A delivery to the plasma membrane. Expression of constitutively active Rho GTPases such as CDC42 (116952), RAC1 (602048), and RhoA (ARHA; 165390) revealed a requirement for CDC42 in the trafficking of ATP7A to the cell surface. Furthermore, overexpression of WASP (300392) inhibited anterograde transport of ATP7A, further supporting regulation by the CDC42 GTPase.
Cobbold et al. (2003) showed that ATP7A is internalized by a novel pathway that is independent of clathrin (see 118960)-mediated endocytosis. Expression of dominant-negative mutants of the dynamin-1 (DNM1; 602377), dynamin-2 (DNM2; 602378), and EPS15 (600051) proteins that block clathrin-dependent endocytosis of the transferrin receptor did not inhibit internalization of endogenous ATP7A or an ATP7A reporter molecule (CD8-MCF1). Similarly, inhibitors of caveolae (see 601047)-mediated uptake did not affect ATP7A internalization and prevented uptake of BODIPY-ganglioside GM1, a caveolae marker. In contrast, expression of a constitutively active mutant of the RAC1 GTPase inhibited plasma membrane internalization of both the ATP7A and transferrin receptor transmembrane proteins. Cobbold et al. (2003) concluded that their findings defined a novel route required for ATP7A internalization and delivery to endosomes.
Schlief et al. (2006) stated that ATP7A is required for production of an NMDA receptor (see GRIN1; 138249)-dependent releasable copper pool within hippocampal neurons, suggesting a role for copper in activity-dependent modulation of synaptic activity. In support of this hypothesis, they found that copper chelation exacerbated NMDA-mediated excitotoxic cell death in rat primary hippocampal neurons, whereas addition of copper was protective and significantly decreased cytoplasmic calcium levels after NMDA receptor activation. The protective effect of copper in hippocampal neurons depended on endogenous nitric oxide production, demonstrating an in vivo link between neuroprotection, copper metabolism, and nitrosylation. Using 'brindled' mice, a model of Menkes disease (see ANIMAL MODEL), Schlief et al. (2006) showed that ATP7A was required for these copper-dependent effects. Hippocampal neurons isolated from newborn brindled mice showed marked sensitivity to endogenous glutamate-mediated NMDA receptor-dependent excitotoxicity in vitro, and mild hypoxic/ischemic insult to these mice in vivo resulted in significantly increased caspase-3 (CASP3; 600636) activation and neuronal injury.
Setty et al. (2008) showed that the pigment cell-specific cuproenzyme tyrosinase acquires copper only transiently and inefficiently within the trans-Golgi network of mouse melanocytes. To catalyze melanin synthesis, tyrosinase is subsequently reloaded with copper within specialized organelles called melanosomes. Copper is supplied to melanosomes by ATP7A, a cohort of which localizes to melanosomes in a BLOC1 (biogenesis of lysosome-related organelles complex-1)-dependent manner. Setty et al. (2008) concluded that cell type-specific localization of a metal transporter is required to sustain metallation of an endomembrane cuproenzyme, providing a mechanism for exquisite spatial control of metalloenzyme activity. Moreover, because BLOC1 subunits are mutated in subtypes of the genetic disease Hermansky-Pudlak syndrome (203300), these results also show that defects in copper transporter localization contribute to hypopigmentation, and hence perhaps other synaptic defects, in Hermansky-Pudlak syndrome.
Crystal Structure
Gourdon et al. (2011) presented the structure of a P-type class IB (PIB) ATPase, a Legionella pneumophila CopA copper ATPase, in a copper-free form, as determined by x-ray crystallography at 3.2-angstrom resolution. The structure indicates a 3-stage copper transport pathway involving several conserved residues. A PIB-specific transmembrane helix kinks at a double-glycine motif displaying an amphipathic helix that lines a putative copper entry point at the intracellular interface. Comparisons to calcium ATPase suggested an ATPase-coupled copper release mechanism from the binding sites in the membrane via an extracellular exit site. Gourdon et al. (2011) suggested that their structure will provide a framework for analysis of missense mutations in human ATP7A and ATP7B (606882) proteins associated with Menkes and Wilson disease (277900), respectively.
Menkes Disease
Kaler et al. (1994) identified mutations in the ATP7A gene in affected members of a family with Menkes disease (300011.0001).
Tumer et al. (1997) examined genomic DNA of 41 unrelated patients affected with the classic severe form of Menkes disease. Using SSCP analysis and direct sequencing of the exons amplified by PCR, they identified a different mutation in each of the 41 patients, including 19 insertion/deletions, 10 nonsense mutations, 4 missense mutations, and 8 splice site alterations. Approximately 90% of the mutations were predicted to result in truncation of the ATP7A protein. In 20 patients the mutations were within exons 7-10, and half of these mutations affected exon 8. Furthermore, 5 alterations were observed within the 6-bp sequence at the splice donor site of intron 8, which would be predicted to affect the efficiency of exon 8 splicing. Tumer et al. (1997) speculated that the region encoded by exon 8 may serve as a 'stalk,' joining its metal-binding domains and its ATPase core.
Poulsen et al. (2002) stated that approximately 15% of mutations causing Menkes disease are partial gene deletions. Poulsen et al. (2002) demonstrated that intragenic polymorphic markers can be used for carrier detection as well as for the identification of affected males.
Moller et al. (2005) identified 21 novel missense mutations in the ATP7A gene in patients with Menkes disease. The mutations were located within the conserved part of ATP7A between residues val842 and ser1404. Molecular 3-dimensional modeling based on the structure of ATP2A1 (108730) showed that the mutations were more spatially clustered than expected from the primary sequence. The authors suggested that some of the mutations may interfere with copper binding.
Moizard et al. (2011) identified pathogenic mutations in the ATP7A gene in 34 (85%) of 40 patients referred for either Menkes disease (38 patients) or occipital horn syndrome (2 patients). There were 23 point mutations, including 9 missense mutations, 7 splice site variants, 4 nonsense mutations, and 3 small insertions or deletions, as well as 7 intragenic deletions. Twenty-one of the mutations were novel, indicating that most mutations are private. In addition, there were 4 whole exon duplications, which expanded the mutational spectrum in the ATP7A gene. Large rearrangements, either deletions or duplications, accounted for 32.4% of the mutations. Most (66.6%) of the point mutations resulted in impaired ATP7A transcript splicing.
Occipital Horn Syndrome
Kaler et al. (1994) identified mutations in the ATP7A gene in a patient with X-linked cutis laxa, also known as occipital horn syndrome (OHS; 304150) (see 300011.0002).
Levinson et al. (1996) detected a small deletion in a region 5-prime to the MNK gene in a patient with occipital horn syndrome. Whereas a normal control had 3 tandem 98-bp repeats upstream of the transcription start site, the patient had a deletion of 1 of the repeats. Although cell lines from the patient showed no reduction in MNK mRNA, there was a decrease in activity of a chloramphenicol acetyltransferase (CAT) reporter gene, suggesting that the repeat sequences may regulate MNK gene expression in the context of a larger region of genomic DNA. Levinson et al. (1996) speculated that their studies of MNK mRNA levels in the patient's cultured cells did not accurately reflect the in vivo situation. The deletion was not identified in 110 control individuals.
Yasmeen et al. (2014) identified 3 different deep intronic mutations in the ATP7A gene in 3 unrelated patients with occipital horn syndrome or Menkes syndrome. The mutations were found by analysis of RNA isolated from patient fibroblasts after no ATP7A mutations were found by standard detection methods. The mutations resulted in the inclusion of pseudoexons between exons 10 and 11, 16 and 17, and 14 and 15, respectively, and were predicted to result in truncated proteins or nonsense-mediated mRNA decay. Although these mutations represented less than 1% of a combined cohort of 501 patients with an ATP7A mutation, the findings in 3 unrelated individuals suggested that this may be an important pathogenetic mechanism in OHS/Menkes syndrome.
X-Linked Distal Spinal Muscular Atrophy 3
In affected members of 2 families with X-linked distal spinal muscular atrophy-3 (SMAX3; 300489), previously reported by Takata et al. (2004) and Kennerson et al. (2009), Kennerson et al. (2010) identified 2 different mutations in the ATP7A gene: T994I (300011.0015) and P1386S (300011.0016), respectively. In vitro functional expression assays indicated that the mutations resulted in impaired copper transport into the secretory pathway for incorporation into nascent proproteins, perhaps due to reduced conformational flexibility. Kennerson et al. (2010) suggested that the late onset of distal muscular atrophy implies that these mutations produced attenuated effects that required years to provoke pathologic consequences. Motor neurons may be particularly sensitive to perturbations in copper homeostasis or copper deficiency, which may impair normal axonal growth and synaptogenesis.
The clinical outcome of copper replacement therapy in Menkes disease in the small number of cases reported has ranged from poor (Kaler et al., 1995) to favorable (Christodoulou et al., 1998). Kim et al. (2003) characterized the biochemical and cell biologic defect associated with an MNK mutation (300011.0010) found in a successfully treated patient (Kaler et al., 1996). The mutation involved the deletion of exon 8 of the ATP7A gene, which encodes a small region between the sixth copper binding site and the first membrane spanning domain of the MNK protein. The mutant protein localized correctly to the TGN and was capable of transporting copper to tyrosinase, a copper-dependent enzyme that is synthesized within secretory compartments. However, in cells exposed to increased copper, the MNK mutant protein failed to traffic to the plasma membrane. This represented the first trafficking defective Menkes disease mutation demonstrated to retain copper transport function, thereby showing that trafficking and transport functions of MNK ATPase can be uncoupled. Thus, certain Menkes disease mutations that inhibit copper-induced trafficking of an otherwise functional copper transporter may be particularly responsive to copper replacement therapy.
Moller et al. (2000) stated that more than 150 point mutations had been identified in the ATP7A gene. Most of these mutations were found to lead to the classic form of Menkes disease, and a few to the milder occipital horn syndrome. They reported 2 Menkes patients and 1 OHS patient with mutations in the splice donor site of intron 6. RT-PCR studies showed that exon 6 was deleted in most ATP7A transcripts of all 3 patients, but RT-PCR amplification with an exon 6-specific primer identified small amounts of exon 6-containing mRNA products from all 3 patients. Direct sequencing showed that only the patient with OHS had correctly spliced exon 6-containing transcripts at levels of 2 to 5% of controls. These findings indicated that the presence of barely detectable amounts of correctly spliced ATP7A transcript is sufficient to permit the development of the milder OHS phenotype, as opposed to classic Menkes disease. The patient with OHS was found to have a mutation at a less conserved position of the donor splice site (300011.0006) compared to 1 of the Menkes patients who had a mutation at a more conserved position of the splice site (300011.0007).
Gu et al. (2001) searched for mutations in the ATP7A gene in 17 unrelated Japanese males with Menkes disease and 2 Japanese males with occipital horn syndrome. In 16 of 17 males with Menkes disease, they identified 16 mutations, including 4 deletions, 2 insertions, 6 nonsense mutations, 2 missense mutations, and 2 splice site mutations. Of 2 males with occipital horn syndrome, 1 had a splice site mutation in intron 6 that led to normal-size and smaller-size transcripts. The amount of the normal-size transcripts in his cultured skin fibroblasts was 19% of the normal level. Serum copper and ceruloplasmin levels were normal, whereas his cultured skin fibroblasts contained increased levels of copper. This patient, first seen at the age of 12 months, had developmental delay, hypotonia, and cutis laxa. Bladder diverticula were detected at age 21 months, and occipital horns at age 6 years.
The 'mottled' (Mo) mouse comprises several phenotypic variations presumed to result from a single X-linked locus. Hemizygous 'pewter' (pew) males have isolated coat color changes; 'blotchy' (blo) males have connective tissue defects; 'brindled' (br) and 'macular' (ml) mice have neurologic disease; and 'dappled' (dp) and 'tortoiseshell' (to) mice have perinatal lethality. For a detailed description of the 'mottled' mouse, a model for Menkes syndrome, see 309400. Levinson et al. (1994) and Mercer et al. (1994) found that 2 variant forms of the mottled mouse, dappled and blotchy, resulted from allelic mutations at the mottled locus. The dappled mutant had no Atp7a mRNA, resulting from a deletion or rearrangement of DNA in the Atp7a gene, and the blotchy mouse mutant had abnormal mRNA expression, likely resulting from a splice site mutation.
Reed and Boyd (1997) identified mutations in the Atp7a gene in the 'viable brindled' (vbr) and 'brindled' mottled mouse mutants. Cecchi et al. (1997) identified mutations in mouse Atp7a that could explain the mottled phenotype in 9 of 10 mutants analyzed. The authors commented that the wide spectrum of mutations detected in the mouse Atp7a gene provided an explanation for at least part of the wide phenotypic variation observed in mottled mutant mice.
Grimes et al. (1997) showed that the 'brindled' mouse has a deletion of 2 amino acids in a highly conserved region of the Atp7a gene. They also presented Western blot data for the normal gene product in tissues. In the kidney, immunohistochemistry demonstrated the protein in proximal and distal tubules, with a distribution identical in mutant and normal mice. This distribution was considered consistent with the protein being involved in copper resorption from the urine.
Haddad et al. (2014) characterized the causative deletion in carrier females of the 'mottled-dappled' (Mo-dp) mouse model of Menkes disease, reported a genotyping assay that identified the colony's different alleles, and assessed the copper-related biochemical phenotype in heterozygous female brains. The deletion consists of a 9-kb deletion in the 5-prime UTR of the Atp7a gene. Affected mutants die in utero at embryonic day (E) 17, and show bending and thickening of the ribs and distortion of the pectoral and pelvic girdles and limbs. Western blot analysis of Mo-dp heterozygous brains showed diminished amounts of Atp7a protein, consistent with reduced expression due to the promoter region deletion on 1 allele. In heterozygous female mice, brain copper levels tended to be lower compared to wildtype, whereas neurochemical analyses revealed higher dihydroxyphenylacetic acid:dihydroxyphenylglycol (DOPAC:DHPG) and dopamine:norepinephrine (DA:NE) ratios compared to normal (p = 0.002 and 0.029, respectively), consistent with partial deficiency of dopamine-beta-hydroxylase, a copper-dependent enzyme. Heterozygous females showed no significant differences in body weight compared to wildtype.
Guthrie et al. (2020) reported that the small molecule elesclomol escorted copper to mitochondria and increased cytochrome c oxidase-1 (COX1, or MTCO1; 516030) levels in brain of mottled-brindled mouse. Through this mechanism, elesclomol prevented detrimental neurodegenerative changes and improved survival of mottled-brindled mouse. Treated mice had normal growth, survival, and improved cardiac Cox1 levels compared with untreated controls. Untreated mice exhibited hypopigmentation and death around postnatal day-14. In contrast, mice treated with elesclomol and copper produced pigment within 24 hours near the injection site and showed wildtype levels of serum copper, reduced but improved levels of brain copper, and wildtype brain weight. Guthrie et al. (2020) concluded that elesclomol holds promise for treatment of Menkes disease and associated disorders of hereditary copper deficiency.
Family A, studied by Kaler et al. (1994), had 4 males with a Menkes disease (309400) phenotype featuring comparatively enhanced longevity and milder neurodevelopmental deficits compared with classic Menkes disease. All 4 affected males were still living at ages 36, 26, 16, and 2 years. The 3 oldest had onset of seizures at ages 4, 8, and 3 years of age, respectively. All 4 had pili torti, bladder diverticula, and striking skin laxity. The 3 oldest had occipital exostoses and chronic diarrhea. In family A, the affected males were found to have a mutation in a splice donor site leading to deletion of 118 nucleotides constituting so-called exon X. An A-to-T transversion at the +3 position resulted in 3 consecutive thymine bases in this splice donor site. Because the mutation did not alter a restriction site in the gene, Kaler et al. (1994) developed a PCR-based assay to screen members of the family for the mutation, using the amplification refractory mutation system (ARMS).
In a 15-year-old male whose clinical and radiographic abnormalities corresponded closely to those compiled in 20 patients with occipital horn syndrome (304150) by Tsukahara et al. (1994), Kaler et al. (1994) identified a 2462A-G transition at the 3-prime end (position -2) of a 92-bp exon in the ATP7A gene, resulting in exon skipping and activation of a cryptic splice acceptor site. Maintenance of some normal splicing was demonstrable by RT-PCR, cDNA sequencing, and ribonuclease protection.
Ronce et al. (1997) observed a family in which 6 males in 5 sibships in 3 generations connected through carrier females who had occipital horn syndrome (304150). Studies of the proband's DNA revealed a 2055C-T transition in exon 8 of the ATP7A gene, resulting in a ser637-to-leu (S637L) substitution. This transition was associated with both normal processing of ATP7A mRNA and exon skipping, with 2 alternatively spliced abnormal products: 1 with only exon 8 skipped and the other with 3 consecutive exons--8, 9, and 10--skipped. Ronce et al. (1997) noted that exon 8, the site of this mutation, appears to be particularly vulnerable to mutations, and referred to a nonsense mutation in the same codon, S637X, that had been reported by Tumer et al. (1997). The fact that the OHS phenotype but not the Menkes (309400) phenotype was observed in this patient could be explained by the presence of the normally processed mRNA and by the likely production of functional ATP7A protein.
The patient reported by Ronce et al. (1997) was suggested to have Ehlers-Danlos syndrome within the first week of birth because of the combination of long length, pectus excavatum, loose skin, and joint laxity. Right and left inguinal hernias were observed from 4 months of age and required repeated surgical interventions. Recurrent urinary bacterial infections revealed bladder diverticula at 15 months of age. Skin biopsies at 5 years of age revealed fragmented collagen fibers and a relative excess of elastic fibers. Normally elevated radiocopper retention was demonstrated in the patient's fibroblasts. At the age of 25 years, the man was tall (181.5 cm), with narrow shoulders, marked pectus excavatum, and dorsal kyphosis, flat feet, loose wrists and finger joints, a weak abdominal wall, soft pinnae, and loose and hyperelastic skin. The hair was kinky, with numerous, although moderate, pili torti. All of the teeth had gray enamel, and the inferior incisors had particular spicules. Skeletal x-rays showed mild occipital exostoses, thickening of muscle insertion zones on the long bones, and irregular shapes of the cubitus and radius, with distortion of the proximal end of the radius and enlargement of the distal end of the tibia. The proband died suddenly at 27 years of age; autopsy showed perforated gastric ulcer and peritonitis. His mother had a long face, large pinnae, and loose skin, which could be interpreted as symptoms of the carrier state.
In a Mexican-American male infant who presented as a neonate with severe congenital cutis laxa (304150), Packman et al. (1997) identified an 8-bp deletion (1552del8) in exon 5 of the ATP7A gene, which encodes the fifth metal-binding domain. The out-of-frame deletion resulted in a downstream premature stop codon. At birth, the child had extremely loose skin, with truncal folds and sagging facial skin, hyperextensible joints, pectus excavatum, craniotabes, and stridor. His hair was sparse and coarse, with frontal balding. Significant neurologic abnormalities were first noted at age 2 months, after which time he showed progressive neurologic deterioration until death at age 13 months. MRI at age 2.5 weeks showed tortuosity and looping of intracranial vessels. Skin biopsy at that time showed fragmented elastin fibers. Serum copper was normal on day 1, but low at age 4 months.
In a patient with lethal neonatal Menkes disease (309400) reported by Jankov et al. (1998), Horn (1999) identified a C-to-T transition in the ATP7A gene, resulting in an arg980-to-ter (R980X) substitution. The child presented as a newborn with acute onset of severe intraabdominal bleeding, hemorrhagic shock, and multiple fractures leading to death at day 27. Menkes disease was diagnosed at autopsy and confirmed by copper accumulation studies on cultured fibroblasts. Such an early onset of fatal complications in Menkes disease had not previously been reported. The R980X mutation was said to have been identical to the mutation found in an unrelated male with Menkes disease who died at the age of 4 years without severe connective tissue disease (Horn, 1999).
In a 24-year-old man with a clinical picture typical of occipital horn syndrome (304150), Moller et al. (2000) identified a T-to-A transversion at the donor splice site of intron 6 of the ATP7A gene. Cell culture studies showed levels of ATP7A transcripts at 2 to 5% of controls. The patient had a narrow thorax, joint deformities, right inguinal hernia, bladder diverticula, vascular abnormalities, and chronic diarrhea. Occipital horns of about 5 cm had been found when he was 18. The patient's skin was dry, loose, and hypopigmented, and his hair was coarse. Complications included aneurysms of abdominal vessels, hepatic artery, and splenic artery which were treated surgically. The patient showed psychomotor retardation, with psychotic characteristics (manic-depressive behavior). He was able to walk without support at age 3 years and started talking at age 3.5 years. Serum copper and ceruloplasmin levels were significantly below normal. Copper-incorporation studies showed abnormal accumulation and retention, confirming that the patient suffered from a variant of Menkes disease. A brother who had similar connective tissue abnormalities and coarse hair, but was more severely retarded, had died at age 8 years (Mentzel et al., 1999).
Moller et al. (2000) described a splice site mutation involving the +1 position of intron 6 of the ATP7A gene in a patient with classic Menkes disease (309400). The patient had shown hypoglycemia and repeated episodes of hypothermia during the neonatal period. At the age of 8 weeks, he was hospitalized because of feeding difficulties that were accompanied by therapy-resistant seizures. At 10 weeks of age, his hair started to fall out and was replaced by hair with an abnormal texture, raising suspicion of Menkes disease. Serum copper and ceruloplasmin levels were very low. Over the next months he developed subdural hematomas, high arched palate, and wormian bones in the lambdoid suture of the occipital region. Bladder diverticula were diagnosed at age 1.5 years. Copper histidine therapy was initiated when he was 8 months old and continued until his death at age 21 years.
In affected members of a family with occipital horn syndrome (304150), Dagenais et al. (2001) identified a 1-bp deletion (4497delG) in exon 23 of the ATP7A gene, resulting in a frameshift at codon 1451 and premature termination of the protein. Although abundant levels of mutant transcript were present, there were substantially reduced levels of the truncated protein, which lacked the key dileucine motif L1487L1488. This dileucine motif functions as an endocytic signal for ATP7A cycling between the trans-Golgi network and the plasma membrane. Steady-state localization of ATP7A to the trans-Golgi network is necessary for proper activity of lysyl oxidase (153455), which is the predominant cuproenzyme whose activity is deficient in OHS and which is essential for maintenance of connective-tissue integrity. The proband in the family reported by Dagenais et al. (2001) sat without assistance at the age of 7 months and was able to crawl at the age of 7.5 months. 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. Skeletal survey showed 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, bilateral coxa valga, and minimal dextroconvex scoliosis. He had an affected brother, a maternal uncle, and a cousin with slight variability in severity.
In transfected cultured cells, Kim et al. (2002) characterized a gly1019-to-asp (G1019D) mutation, located in the large cytoplasmic loop of the MNK protein, that causes Menkes disease (309400). In copper-limiting conditions, the G1019D mutant protein was retained in the endoplasmic reticulum. This mislocalization was corrected by the addition of copper to cells via a process that was dependent upon the copper-binding sites at the N-terminal region of the MNK protein. Reduced growth temperature and the chemical chaperone glycerol corrected the mislocalization of the G1019D mutant, suggesting that this mutation interferes with protein folding in the secretory pathway. These findings identified G1019D as the first conditional mutation associated with Menkes disease and demonstrated correction of the mislocalized protein by copper supplementation. The findings provided a molecular framework for understanding how mutations that affect the proper folding of the MNK transporter in Menkes patients may be responsive to parenteral copper therapy.
Kaler et al. (1996) described successful early copper therapy in Menkes disease (309400) associated with a mutant transcript containing a small in-frame deletion. This splice site mutation resulted in deletion of exon 8, which encodes a small region between the sixth copper binding site and the first membrane-spanning domain of MNK protein. Kim et al. (2003) demonstrated that the mutant protein was defective in copper-induced trafficking but its copper transport mutant function was retained. The sequence of exon 8 was deleted from the mutant protein extended between serine-624 and glutamine-649 that was deleted in the in-frame transcript of the patient and replaced by 624 ile-arg.
In a child with classic Menkes disease (309400) and an unusual finding of early occipital horns, Gerard-Blanluet et al. (2004) identified an 8-bp deletion (408delCAATCAGA) in the ATP7A gene, resulting in a frameshift starting at amino acid 136, addition of 21 aberrant amino acids, and loss of the 1,363 amino acids of the C-terminal sequence. They presented hypotheses concerning the occurrence of the rare feature of occipital horn.
Tumer et al. (2003) reported 2 patients with Menkes disease (309400) with unexpectedly mild symptoms and long survival. The proband was 27 years old and his affected maternal cousin 24 years at the time of the report. The proband showed developmental delay at age 6 months and at age 2 years began having seizures. At age 4 years, he developed head control, and, at age 9 years, his motor and mental status was assumed to be like that of a 3-month-old child. At age 17 years, he had no speech, was hypotonic, and had brown, coarse hair. Both the proband and his cousin with the same less-severe symptoms had a deletion in the ATP7A gene encompassing exons 3 and 4.
Paulsen et al. (2006) investigated the functional effect of the large frameshift deletion in ATP7A including exons 3 and 4 identified in a patient with Menkes disease with unexpectedly mild symptoms and long survival (Tumer et al., 2003). The mutated transcript contained a premature termination codon after 46 codons. Although such transcripts are generally degraded by nonsense-mediated mRNA decay (NMD), it was established by real-time PCR quantification that the transcript in this instance was protected from degradation. A combination of in vitro translation, recombinant expression, and immunocytochemical analysis provided evidence that the mutant transcript was protected from degradation because of reinitiation of protein translation. The findings suggested that reinitiation takes place at 2 downstream internal codons. The putative N terminally truncated proteins contained only copper-binding site 5 (CBS5) and CBS6. Cellular localization and copper-dependent trafficking of the major part of endogenous and recombinant ATP7 mutant proteins were similar to the wildtype ATP7A protein. Furthermore, the mutant cDNA was able to rescue a yeast strain lacking the homologous gene, CCC2. In summary, Paulsen et al. (2006) proposed that reinitiation of the NMD-resistant mutant transcript leads to the synthesis of N terminally truncated and at least partially functional Menkes proteins missing CBS1 through CBS4. Thus a mutation that would have been assumed to be null is not.
In 2 brothers with occipital horn syndrome (304150) and their carrier mother, Tang et al. (2006) identified an A-to-G transition at nucleotide 4056 in exon 20 of the ATP7A gene, resulting in an asparagine-to-serine substitution at codon 1304 (N1304S). This mutation was not identified in 50 normal control chromosomes. Tang et al. (2006) showed evidence of 33% residual copper transport by the N1304S mutant allele in a yeast complementation assay.
In a boy with Menkes disease (309400) and unusually favorable response to early copper treatment, Kaler et al. (2009) identified a 746C-T transition in exon 3 of the ATP7A gene, resulting in an arg201-to-ter (R201X) substitution. Western blot analysis of patient fibroblasts showed small amounts of the full-length 178-kD protein. In vitro studies in yeast showed that the mutant protein retained functional copper transport activity. Overall, the findings indicated a read-through of the stop codon. Comparison with other yeast genes that show such read-through mechanisms suggested that unique 5-prime sequences have a role in nonsense suppression, and that mRNA structure may modulate competition between eukaryotic release factors and suppressor tRNA. The findings were consistent with the dramatic clinical response to treatment in this patient, who was neurologically normal at age 11.5 years.
In 10 affected males from a large Brazilian family with X-linked distal hereditary motor neuronopathy (HMNX; 300489), Kennerson et al. (2010) identified a hemizygous c.2981C-T transition in exon 15 of the ATP7A gene, resulting in a thr994-to-ile (T994I) substitution in a highly conserved residue in the C terminus of the protein that did not disrupt critical functional domains. The mutation was not found in 800 ethnically matched controls. The family had previously been reported by Takata et al. (2004). Immunocytochemical studies showed that the T994I-mutant protein had impaired intracellular trafficking compared to control, with some of the mutant protein remaining in the Golgi apparatus after exposure to copper. The findings suggested that the mutation resulted in impaired copper transport into the secretory pathway for incorporation into nascent proproteins, perhaps due to reduced conformational flexibility. Kennerson et al. (2010) suggested that the late onset of distal muscular atrophy implies that the T994I mutation produced attenuated effects that required years to provoke pathologic consequences. Motor neurons may be particularly sensitive to perturbations in copper homeostasis or copper deficiency, which may impair normal axonal growth and synaptogenesis.
In 9 affected males from a large North American family with X-linked distal hereditary motor neuronopathy (HMNX; 300489), previously reported by Kennerson et al. (2009), Kennerson et al. (2010) identified a hemizygous c.4156C-T transition in exon 22 of the ATP7A gene, resulting in a pro1386-to-ser (P1386S) substitution in a highly conserved residue in the C terminus. The mutation was not found in 800 ethnically matched controls. Immunocytochemical analyses showed that the P1386S-mutant protein demonstrated impaired intracellular trafficking compared to control, with some mutant protein remaining in the Golgi apparatus after exposure to copper. Cultured fibroblasts carrying the P1386S mutation had steady-state copper levels that were intermediate between normal control and classic Menkes disease (309400). The growth of yeast transformed with the P1386S allele was less than that of wildtype at all temperatures. The findings suggested that the mutation resulted in impaired copper transport into the secretory pathway for incorporation into nascent proproteins, perhaps due to reduced conformational flexibility. Kennerson et al. (2010) suggested that the late onset of distal muscular atrophy implies that the P1386S mutation produced attenuated effects that required years to provoke pathologic consequences. Motor neurons may be particularly sensitive to perturbations in copper homeostasis or copper deficiency, which may impair normal axonal growth and synaptogenesis.
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