-
Indian Pediatrics Jan 2016
Topics: Cerebral Veins; Humans; Infant; Male; Menkes Kinky Hair Syndrome
PubMed: 26840692
DOI: No ID Found -
Disease Models & Mechanisms Jan 2016The deleterious effects of a disrupted copper metabolism are illustrated by hereditary diseases caused by mutations in the genes coding for the copper transporters ATP7A...
The deleterious effects of a disrupted copper metabolism are illustrated by hereditary diseases caused by mutations in the genes coding for the copper transporters ATP7A and ATP7B. Menkes disease, involving ATP7A, is a fatal neurodegenerative disorder of copper deficiency. Mutations in ATP7B lead to Wilson disease, which is characterized by a predominantly hepatic copper accumulation. The low incidence and the phenotypic variability of human copper toxicosis hamper identification of causal genes or modifier genes involved in the disease pathogenesis. The Labrador retriever was recently characterized as a new canine model for copper toxicosis. Purebred dogs have reduced genetic variability, which facilitates identification of genes involved in complex heritable traits that might influence phenotype in both humans and dogs. We performed a genome-wide association study in 235 Labrador retrievers and identified two chromosome regions containing ATP7A and ATP7B that were associated with variation in hepatic copper levels. DNA sequence analysis identified missense mutations in each gene. The amino acid substitution ATP7B:p.Arg1453Gln was associated with copper accumulation, whereas the amino acid substitution ATP7A:p.Thr327Ile partly protected against copper accumulation. Confocal microscopy indicated that aberrant copper metabolism upon expression of the ATP7B variant occurred because of mis-localization of the protein in the endoplasmic reticulum. Dermal fibroblasts derived from ATP7A:p.Thr327Ile dogs showed copper accumulation and delayed excretion. We identified the Labrador retriever as the first natural, non-rodent model for ATP7B-associated copper toxicosis. Attenuation of copper accumulation by the ATP7A mutation sheds an interesting light on the interplay of copper transporters in body copper homeostasis and warrants a thorough investigation of ATP7A as a modifier gene in copper-metabolism disorders. The identification of two new functional variants in ATP7A and ATP7B contributes to the biological understanding of protein function, with relevance for future development of therapy.
Topics: Adenosine Triphosphatases; Amino Acid Sequence; Animals; Cation Transport Proteins; Copper; Copper-Transporting ATPases; Disease Models, Animal; Dogs; Endoplasmic Reticulum; Female; Genetic Variation; Genome-Wide Association Study; Genotype; Hep G2 Cells; Hepatolenticular Degeneration; Humans; Liver; Male; Menkes Kinky Hair Syndrome; Molecular Sequence Data; Mutation, Missense; Phenotype; Protein Structure, Tertiary; Sequence Analysis, DNA; Sequence Homology, Amino Acid
PubMed: 26747866
DOI: 10.1242/dmm.020263 -
Revista Da Associacao Medica Brasileira... 2015Menkes disease is a congenital disorder caused by changes in copper metabolism derived from mutations in the ATP7A gene. It is characterized by physical and neurological...
Menkes disease is a congenital disorder caused by changes in copper metabolism derived from mutations in the ATP7A gene. It is characterized by physical and neurological alterations. In the neonatal period, these alterations can be nonspecific, which makes early diagnosis a challenge. Diagnosis can be suspected when there are low levels of ceruloplasmin and serum copper. Molecular analysis confirms the diagnosis. Treatment is parenteral administration of copper histidine. We report a familial case with molecular confirmation. The proband had clinical and biochemical suspicious. Treatment with copper histidine was indicated, but initiated at the age of 2 months and 27 days only. He did not present improvements and died at 6 months. The mother became pregnant again, a male fetus was identified and copper histidine was manufactured during pregnancy. He was born healthy, biochemical markers were reduced and treatment was indicated. Molecular analysis was performed confirming mutation in both the mother and the proband, while the other son did not have mutation, so treatment was discontinued. We support the clinical relevance of molecular confirmation for the correct diagnosis and genetic counseling, once clinical findings in the neonatal period are nonspecific and early treatment with parenteral copper histidine must be indicated.
Topics: Adenosine Triphosphatases; Cation Transport Proteins; Ceruloplasmin; Copper; Copper-Transporting ATPases; Fatal Outcome; Female; Hair Diseases; Histidine; Humans; Infant, Newborn; Male; Menkes Kinky Hair Syndrome; Molecular Diagnostic Techniques; Organometallic Compounds; Pregnancy
PubMed: 26603002
DOI: 10.1590/1806-9282.61.05.407 -
American Journal of Physiology. Cell... Dec 2015
Topics: Adenosine Triphosphatases; Animals; Cation Transport Proteins; Copper; Female; Male; Menkes Kinky Hair Syndrome
PubMed: 26468209
DOI: 10.1152/ajpcell.00258.2015 -
Stem Cell Research & Therapy Sep 2015Bone abnormalities, one of the primary manifestations of Menkes disease (MD), include a weakened bone matrix and low mineral density. However, the molecular and cellular...
INTRODUCTION
Bone abnormalities, one of the primary manifestations of Menkes disease (MD), include a weakened bone matrix and low mineral density. However, the molecular and cellular mechanisms underlying these bone defects are poorly understood.
METHODS
We present in vitro modeling for impaired osteogenesis in MD using human induced pluripotent stem cells (iPSCs) with a mutated ATP7A gene. MD-iPSC lines were generated from two patients harboring different mutations.
RESULTS
The MD-iPSCs showed a remarkable retardation in CD105 expression with morphological anomalies during development to mesenchymal stem cells (MSCs) compared with wild-type (WT)-iPSCs. Interestingly, although prolonged culture enhanced CD105 expression, mature MD-MSCs presented with low alkaline phosphatase activity, reduced calcium deposition in the extracellular matrix, and downregulated osteoblast-specific genes during osteoblast differentiation in vitro. Knockdown of ATP7A also impaired osteogenesis in WT-MSCs. Lysyl oxidase activity was also decreased in MD-MSCs during osteoblast differentiation.
CONCLUSIONS
Our findings indicate that ATP7A dysfunction contributes to retardation in MSC development and impairs osteogenesis in MD.
Topics: Adenosine Triphosphatases; Animals; Antigens, CD; Cation Transport Proteins; Cells, Cultured; Copper-Transporting ATPases; Endoglin; Extracellular Matrix; Humans; Induced Pluripotent Stem Cells; Infant; Infant, Newborn; Menkes Kinky Hair Syndrome; Mice; Mutation; Osteogenesis; Protein-Lysine 6-Oxidase; Receptors, Cell Surface
PubMed: 26347346
DOI: 10.1186/s13287-015-0147-5 -
American Journal of Physiology. Cell... Nov 2015Menkes disease is a fatal neurodegenerative disorder arising from a systemic copper deficiency caused by loss-of-function mutations in a ubiquitously expressed copper...
Menkes disease is a fatal neurodegenerative disorder arising from a systemic copper deficiency caused by loss-of-function mutations in a ubiquitously expressed copper transporter, ATP7A. Although this disorder reveals an essential role for copper in the developing human nervous system, the role of ATP7A in the pathogenesis of signs and symptoms in affected patients, including severe mental retardation, ataxia, and excitotoxic seizures, remains unknown. To directly examine the role of ATP7A within the central nervous system, we generated Atp7a(Nes) mice, in which the Atp7a gene was specifically deleted within neural and glial cell precursors without impairing systemic copper homeostasis, and compared these mice with the mottled brindle (mo-br) mutant, a murine model of Menkes disease in which Atp7a is defective in all cells. Whereas mo-br mice displayed neurodegeneration, demyelination, and 100% mortality prior to weaning, the Atp7a(Nes) mice showed none of these phenotypes, exhibiting only mild sensorimotor deficits, increased anxiety, and susceptibility to NMDA-induced seizure. Our results indicate that the pathophysiology of severe neurological signs and symptoms in Menkes disease is the result of copper deficiency within the central nervous system secondary to impaired systemic copper homeostasis and does not arise from an intrinsic lack of ATP7A within the developing brain. Furthermore, the sensorimotor deficits, hypophagia, anxiety, and sensitivity to NMDA-induced seizure in the Atp7a(Nes) mice reveal unique autonomous requirements for ATP7A in the nervous system. Taken together, these data reveal essential roles for copper acquisition in the central nervous system in early development and suggest novel therapeutic approaches in affected patients.
Topics: Adenosine Triphosphatases; Animals; Cation Transport Proteins; Copper; Copper-Transporting ATPases; Female; Gene Expression Regulation; Integrases; Male; Menkes Kinky Hair Syndrome; Mice; Mice, Knockout; Mutation
PubMed: 26269458
DOI: 10.1152/ajpcell.00130.2015 -
American Journal of Medical Genetics.... Nov 2015Menkes disease (MD) is a rare X-linked recessive disorder caused by mutations in the ATP7A gene. This neurodegenerative disorder typically affects males and is...
Menkes disease (MD) is a rare X-linked recessive disorder caused by mutations in the ATP7A gene. This neurodegenerative disorder typically affects males and is characterized by impaired copper distribution and the malfunction of several copper-dependent enzymes. We report clinically discordant female monozygotic twins (MZT) with a heterozygous ATP7A mutation. One twin girl is healthy at the current age of 4 years, whereas the other twin girl developed classical MD, showed disease stabilization under copper histidine treatment but died at the age of 3 years. Presumably, the affected girl developed MD due to skewed X inactivation, although this could not be demonstrated in two tissues (blood, buccal mucosa). This case is a rare example of an affected girl with MD and shows the possibility of a discordant phenotype in MZT girls. As speculated in other X-linked diseases, the process of monozygotic twinning may be associated with skewed X inactivation leading to a discordant phenotype.
Topics: Brain; Child, Preschool; Fatal Outcome; Female; Humans; Infant; Infant, Newborn; Magnetic Resonance Imaging; Menkes Kinky Hair Syndrome; Phenotype; Twins, Monozygotic
PubMed: 26239182
DOI: 10.1002/ajmg.a.37276 -
Hospital Pediatrics Apr 2015
Topics: Copper; Diagnosis, Differential; Early Diagnosis; Failure to Thrive; Humans; Hypothermia; Infant, Newborn; Injections; Lethargy; Male; Menkes Kinky Hair Syndrome
PubMed: 25832979
DOI: 10.1542/hpeds.2014-0118 -
Pediatrics and Neonatology Feb 2017Menkes disease is a rare neurodegenerative disorder caused by mutations in ATP7A gene. Deficiency in copper-dependent enzymes results in the unique kinky hair...
Menkes disease is a rare neurodegenerative disorder caused by mutations in ATP7A gene. Deficiency in copper-dependent enzymes results in the unique kinky hair appearance, neurodegeneration, developmental delay, seizures, failure to thrive and other connective tissue or organ abnormalities. Other than biochemical tests, DNA-based diagnosis is now playing an important role. More than two hundred mutations in ATP7A gene were identified. Early copper supplementation can help improve neurological symptoms, but not non-neurological problems. Further molecular studies are needed to identify additional mutation types and to understand the mechanism of pathogenesis. This may help in discovering the possible treatment measures to cure the disease. We present a case with the clinical features and biochemical findings, abnormal brain magnetic resonance imaging as well as the effects of treatment with copper-histidine. Direct sequencing of ATP7A gene revealed a de novo point mutation which resulted in an early stop codon with truncated protein.
Topics: Adenosine Triphosphatases; Cation Transport Proteins; Copper-Transporting ATPases; Histidine; Humans; Infant; Male; Menkes Kinky Hair Syndrome; Organometallic Compounds; Point Mutation
PubMed: 25771438
DOI: 10.1016/j.pedneo.2014.05.008 -
Neurobiology of Disease Sep 2015ATP7A mutations impair copper metabolism resulting in three distinct genetic disorders in humans. These diseases are characterized by neurological phenotypes ranging... (Review)
Review
ATP7A mutations impair copper metabolism resulting in three distinct genetic disorders in humans. These diseases are characterized by neurological phenotypes ranging from intellectual disability to neurodegeneration. Severe ATP7A loss-of-function alleles trigger Menkes disease, a copper deficiency condition where systemic and neurodegenerative phenotypes dominate clinical outcomes. The pathogenesis of these manifestations has been attributed to the hypoactivity of a limited number of copper-dependent enzymes, a hypothesis that we refer as the oligoenzymatic pathogenic hypothesis. This hypothesis, which has dominated the field for 25 years, only explains some systemic Menkes phenotypes. However, we argue that this hypothesis does not fully account for the Menkes neurodegeneration or neurodevelopmental phenotypes. Here, we propose revisions of the oligoenzymatic hypothesis that could illuminate the pathogenesis of Menkes neurodegeneration and neurodevelopmental defects through unsuspected overlap with other neurological conditions including Parkinson's, intellectual disability, and schizophrenia.
Topics: Adenosine Triphosphatases; Animals; Cation Transport Proteins; Computational Biology; Copper-Transporting ATPases; Humans; Menkes Kinky Hair Syndrome; Mice; Mutation; Neurodegenerative Diseases; Neurodevelopmental Disorders
PubMed: 25583185
DOI: 10.1016/j.nbd.2014.12.024