ATP7A Clinical Genetics Resource – A comprehensive clinically annotated database and resource for genetic variants in ATP7A gene

Mhaske, Aditi; Dileep, Kalarickal V.; Kumar, Mukesh; Poojary, M. Damodara; Pandhare, Kavita; Zhang, Kam Y. J.; Scaria, Vinod; Binukumar, B.

doi:10.1016/j.csbj.2020.08.021

Cited by 6 publications

(6 citation statements)

References 77 publications

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“… 54 ATPase copper transporting alpha (ATP7A) is a critical copper transporter involved in some X linked genetic disorders, such as Menkes disease, occipital horn syndrome and type 3 X‐linked distal spinal muscular atrophy. 55 Protocadherin related 15 ( PCDH15 ) is associated with nonsyndromic deafness and type 1 Usher syndrome. 56 Muscle skeletal receptor tyrosine kinase ( MUSK ) is the pathogenic gene of congenital myasthenic syndrome.…”

Section: Discussionmentioning

confidence: 99%

Copy number variation characterization and possible candidate genes in miscarriage and stillbirth by next‐generation sequencing analysis

Zhang

Huang

et al. 2021

The Journal of Gene Medicine

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Background: The present study aimed to explore the etiological relationship between miscarriage and stillbirth and copy number variations (CNVs), as well as provide useful genetic guidance for high-risk pregnancy.Methods: In total, 659 fetal samples were recruited and subjected to DNA extraction and CNV sequencing (CNV-seq), relevant medical records were collected.Results: There were 322 cases (48.86%) with chromosomal abnormalities, including 230 with numerical abnormalities and 92 with structural abnormalities. Chromosomal monosomy variations mainly occurred on sex chromosomes and trisomy variations mainly occurred on chromosomes 16, 22, 21, 18, 13 and 15. In total, 41 pathogenic CNVs (23 microdeletions and 18 microduplications) were detected in 27 fetal tissues.The rates of numerical chromosomal abnormalities were 29.30% (109/372), 32.39% (57/176) and 57.66% (64/111) in < 30-year-old, 30-34-year-old and ≥ 35-year-old age pregnant women, respectively, and increased with an increasing age (p < 0.001).There was statistically significant difference (χ 2 = 7.595, p = 0.022) in the rates of structural chromosomal abnormalities in these groups (13.71%, 18.75% and 7.21%, respectively). The rates of numerical chromosomal abnormalities were 45.44% (219/482), 7.80% (11/141) and 0% (0/36) in the ≤ 13 gestational weeks, 14-27 weeks and ≥ 28 weeks groups, respectively, and decreased with respect to the increasing gestational age of the fetuses (p < 0.001). Conclusions:The present study has obtained useful and accurate genetic etiology information that will provide useful genetic guidance for high-risk pregnancies.

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Section: Discussionmentioning

confidence: 99%

Copy number variation characterization and possible candidate genes in miscarriage and stillbirth by next‐generation sequencing analysis

Zhang

Huang

et al. 2021

The Journal of Gene Medicine

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“…One mutation was found at nucleotide position1951 (NM_001109757) in exon 7 ( Figure 2A, B ), which was heterozygous for G and T. The G changes the amino acid at position 610 from an isoleucine to a serine (NP_001103227; this corresponds to human amino acid 618, NP_000043). More than 400 nonsense, missense and insertions/deletions have been idenitifed in the human ATP7a gene; those associated with Menkes disease are within the protein coding sequence and map to the copper associated domains, ATPase or transmembrane domains in particular 41 . In the two parental strains used in the mutagenesis protocol, 129S6 and C57BL6/J, the nucleotide at position 1951 is a T ( Figure 2C, D ).…”

Section: Resultsmentioning

confidence: 99%

Alpha-synuclein null mutation exacerbates the phenotype of a model of Menkes disease in female mice

Casey,

Zou,

Pera

et al. 2023

Preprint

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Genetic modifier screens provide a useful tool, in diverse organisms fromDrosophilatoC. elegansand mice, for recovering new genes of interest that may reduce or enhance a phenotype of interest. This study reports a modifier screen, based on N-ethyl-N-nitrosourea (ENU) mutagenesis and outcrossing, designed to increase understanding of the normal function of murine α-synuclein (Snca). HumanSNCAwas the first gene linked to familial Parkinson’s disease. Since the discovery of the genetic link ofSNCAto Parkinson’s nearly three decades ago, numerous studies have investigated the normal function of SNCA protein with divergent roles associated with different cellular compartments. Understanding of the normal function of murine Snca is complicated by the fact that mice with homozygous null mutations live a normal lifespan and have only subtle synaptic deficits. Here, we report that the first genetic modifier (a sensitized mutation) that was identified in our screen was the X-linked gene,ATPase copper transporting alpha (Atp7a).In humans, mutations inAtp7aare linked to to Menkes disease, a disease with pleiotropic phenotypes that include a severe neurological component.Atp7aencodes a trans-Golgi copper transporter that supplies the copper co-factor to enzymes that pass through the ER-Golgi network. Male mice that carry a mutation inAtp7adie within 3 weeks of age regardless ofSncagenotype. In contrast, here we show thatSncadisruption modifies the phenotype ofAtp7ain female mice. Female mice that carry theAtp7amutation, on anSncanull background, die earlier (prior to 35 days) at a significantly higher rate than those that carry theAtp7amutation on a wildtypeSncabackground ATPase copper transporting alpha. Thus,Sncanull mutations sensitize female mice to mutations inAtp7a,suggesting that Snca protein may have a protective effect in females, perhaps in neurons, given the co-expression patterns. Although data has suggested diverse functions for human and mouse α-synuclein proteins in multiple cell compartments, this is the first demonstration via use of genetic screening to demonstrate that Snca protein may function in the ER-Golgi system in the mammalian brain in a sex-dependent manner.Author summaryThis study sought to probe the normal function(s) of a protein associated with Parkinson’s disease, the second most common neurodegenerative disease in humans. We used a genetic modifier approach to uncover aspects of normal protein function, via mutagenesis of mice and screening for neurological problems that are decreased or enhanced in mice that are null for α-synuclein (Snca). Through these studies, we identified the X-linked gene that is mutated in Menkes disease in humans as a modifier of the nullSncaphenotype, specifically in female mice. The gene mutated in Menkes disease,ATP7a, encodes a copper transporter that is known to act in the trans-Golgi sub-cellular compartment. Genetic modifier effects suggest that Snca may also play a role in that compartment, potentially in the mammalian brain.

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“…The majority of variants identified in ATP7A have been identified in patients with Menkes disease. Following variant classification analysis of ATP7A variants by Mhaske et al (2020) , of the pathogenic and likely pathogenic variants in ATP7A, 89 % were identified in patients with Menkes disease, with just 4 % in OHS ( Mhaske et al, 2020 ). However, in reports from a single Danish center, there are similar proportions of patients with missense, nonsense, indel, and splice site variants in ATP7A ( Møller, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

“…Menkes disease is the most clinically severe disease on an allelic spectrum of ATP7A -related disorders, which includes occipital horn syndrome (OHS; MIM 304150 ), and X-linked distal spinal muscular atrophy type 3 (SMAX3; MIM 300489 ) ( Fradin et al, 2020 ; Zlatic et al, 2015 ). The severity of disease largely correlates to the deleteriousness of the causal ATP7A variant ( Mhaske et al, 2020 ). Nonsense variants and large deletions correlate with an absence of functional protein, and cause Menkes disease, which manifest from the first few months of life.…”

Section: Introductionmentioning

confidence: 99%

Deep intronic variant causes aberrant splicing of ATP7A in a family with a variable occipital horn syndrome phenotype

Harkness,

Thomas,

Urquhart

et al. 2024

European Journal of Medical Genetics

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ATP7A Clinical Genetics Resource – A comprehensive clinically annotated database and resource for genetic variants in ATP7A gene

Abstract: Graphical abstract

Cited by 6 publications

References 77 publications

Copy number variation characterization and possible candidate genes in miscarriage and stillbirth by next‐generation sequencing analysis

Copy number variation characterization and possible candidate genes in miscarriage and stillbirth by next‐generation sequencing analysis

Alpha-synuclein null mutation exacerbates the phenotype of a model of Menkes disease in female mice

Deep intronic variant causes aberrant splicing of ATP7A in a family with a variable occipital horn syndrome phenotype

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