Unstable argininosuccinate lyase in variant forms of the urea cycle disorder argininosuccinic aciduria

Hu, Liyan; Pandey, Amit V.; Balmer, Cécile; Eggimann, Sandra; Rüfenacht, Véronique; Nuoffer, Jean-Marc; Häberle, Johannes

doi:10.1007/s10545-014-9807-3

“…; Hu et al. ). This gene, along with some of 274 other genes we found annotated for nitrogen metabolism, may show parallel changes in expression between specialists as an adaptation to nitrogen‐rich diets (Martin ).…”

Section: Discussionmentioning

confidence: 98%

“…For example, the gene asl (argininosuccinate lyase) is important for nitrogen excretion. Variants of asl are associated with argininosuccinic aciduria and citrullinemia, conditions involving an accumulation of ammonia in the blood (Saheki et al 1987;Hu et al 2015). This gene, along with some of 274 other genes we found annotated for nitrogen metabolism, may show parallel changes in expression between specialists as an adaptation to nitrogen-rich diets (Martin 2016b).…”

Section: Adaptationsmentioning

confidence: 89%

Parallel evolution of gene expression between trophic specialists despite divergent genotypes and morphologies

McGirr

¹

,

Martin

²

2018

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Parallel evolution of gene expression commonly underlies convergent niche specialization, but parallel changes in expression could also underlie divergent specialization. We investigated divergence in gene expression and whole‐genome genetic variation across three sympatric Cyprinodon pupfishes endemic to San Salvador Island, Bahamas. This recent radiation consists of a generalist and two derived specialists adapted to novel niches: a scale‐eating and a snail‐eating pupfish. We sampled total mRNA from all three species at two early developmental stages and compared gene expression with whole‐genome genetic differentiation among all three species in 42 resequenced genomes. Eighty percent of genes that were differentially expressed between snail‐eaters and generalists were up or down regulated in the same direction between scale‐eaters and generalists; however, there were no fixed variants shared between species underlying these parallel changes in expression. Genes showing parallel evolution of expression were enriched for effects on metabolic processes, whereas genes showing divergent expression were enriched for effects on cranial skeleton development and pigment biosynthesis, reflecting the most divergent phenotypes observed between specialist species. Our findings reveal that even divergent niche specialists may exhibit convergent adaptation to higher trophic levels through shared genetic pathways. This counterintuitive result suggests that parallel evolution in gene expression can accompany divergent ecological speciation during adaptive radiation.

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“…However, all patients with late-onset phenotype were diagnosed before 20 months of life. p.(Arg385Cys) has been reported as a founder mutation in the Finnish population (Keskinen et al 2008) and is associated with very low ASL activity affecting an amino acid near the catalytic site (Hu et al 2015). …”

Section: Discussionmentioning

confidence: 99%

Expanding the phenotype in argininosuccinic aciduria: need for new therapies

Baruteau

¹

,

Jameson

²

,

Morris

³

et al. 2017

J of Inher Metab Disea

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ObjectivesThis UK-wide study defines the natural history of argininosuccinic aciduria and compares long-term neurological outcomes in patients presenting clinically or treated prospectively from birth with ammonia-lowering drugs.MethodsRetrospective analysis of medical records prior to March 2013, then prospective analysis until December 2015. Blinded review of brain MRIs. ASL genotyping.ResultsFifty-six patients were defined as early-onset (n = 23) if symptomatic < 28 days of age, late-onset (n = 23) if symptomatic later, or selectively screened perinatally due to a familial proband (n = 10). The median follow-up was 12.4 years (range 0–53). Long-term outcomes in all groups showed a similar neurological phenotype including developmental delay (48/52), epilepsy (24/52), ataxia (9/52), myopathy-like symptoms (6/52) and abnormal neuroimaging (12/21). Neuroimaging findings included parenchymal infarcts (4/21), focal white matter hyperintensity (4/21), cortical or cerebral atrophy (4/21), nodular heterotopia (2/21) and reduced creatine levels in white matter (4/4). 4/21 adult patients went to mainstream school without the need of additional educational support and 1/21 lives independently. Early-onset patients had more severe involvement of visceral organs including liver, kidney and gut. All early-onset and half of late-onset patients presented with hyperammonaemia. Screened patients had normal ammonia at birth and received treatment preventing severe hyperammonaemia. ASL was sequenced (n = 19) and 20 mutations were found. Plasma argininosuccinate was higher in early-onset compared to late-onset patients.ConclusionsOur study further defines the natural history of argininosuccinic aciduria and genotype–phenotype correlations. The neurological phenotype does not correlate with the severity of hyperammonaemia and plasma argininosuccinic acid levels. The disturbance in nitric oxide synthesis may be a contributor to the neurological disease. Clinical trials providing nitric oxide to the brain merit consideration.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-017-0022-x) contains supplementary material, which is available to authorized users.

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“…For example, the gene asl (argininosuccinate lyase) is 558 important for nitrogen excretion. Variants of asl are associated with argininosuccinic aciduria 559 and citrullinemia, conditions involving an accumulation of ammonia in the blood (Saheki et al 560 1987;Hu et al 2015). This gene, along with some of 274 other genes we found annotated for 561 nitrogen metabolism, may show parallel changes in expression between specialists as an 562 adaptation to nitrogen-rich diets (Martin 2016b).…”

Section: Candidate Genes Influencing Trophic Adaptations 554mentioning

confidence: 93%

Parallel evolution of gene expression between trophic specialists despite divergent genotypes and morphologies

McGirr

¹

,

Martin

²

2017

Preprint

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Parallel evolution of gene expression commonly underlies convergent niche specialization, but parallel changes in expression could also underlie divergent specialization. We investigated divergence in gene expression and whole-genome genetic variation across three sympatric Cyprinodon pupfishes endemic to San Salvador Island, Bahamas. This recent radiation consists of a generalist and two derived specialists adapted to novel niches – a ‘scale-eater’ and a ‘snail-eater.’ We sampled total mRNA from all three species at two early developmental stages and compared gene expression with whole-genome genetic differentiation among all three species in 42 resequenced genomes. 80% of genes that were differentially expressed between snail-eaters and generalists were up or downregulated in the same direction between scale-eaters and generalists; however, there were no fixed variants shared between species underlying these parallel changes in expression. Genes showing parallel evolution of expression were enriched for effects on metabolic processes, whereas genes showing divergent expression were enriched for effects on cranial skeleton development and pigment biosynthesis, reflecting the most divergent phenotypes observed between specialist species. Our findings reveal that even divergent niche specialists may exhibit convergent adaptation to higher trophic levels through shared genetic pathways. This counterintuitive result suggests that parallel evolution in gene expression can accompany divergent ecological speciation during adaptive radiation.Impact SummaryAdaptations that result in unique forms of ecological specialization are central to research in evolutionary biology, yet little is known about their molecular foundations. We combined transcriptome sequencing with whole-genome divergence scans to study the molecular evolution of two specialist Cyprinodon pupfish species – a ‘scale-eater’ and a ‘snail-eater’ – that rapidly diverged from a sympatric generalist ancestor within the last 10,000 years. While parallel evolution of gene expression driving convergent niche specialization seems common, we present, to our knowledge, the first example of significant parallel changes in expression coinciding with divergent niche specialization. 80% of genes that were differentially expressed between snail-eaters and generalists showed the same direction of expression in scale-eaters relative to generalists. Furthermore, parallel evolution in expression seem to be controlled by unique genetic variants in each specialist species. Genes showing parallel changes in expression were enriched for metabolic processes that may facilitate adaptation to a higher trophic level, while genes showing divergent expression likely shape the striking morphological differences between specialists. These findings contribute to a more nuanced understanding of convergent adaptations that arise during speciation, and highlight how species can evolve similar expression profiles adapted to divergent niches.

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Unstable argininosuccinate lyase in variant forms of the urea cycle disorder argininosuccinic aciduria

Cited by 17 publications

References 51 publications

Parallel evolution of gene expression between trophic specialists despite divergent genotypes and morphologies

Parallel evolution of gene expression between trophic specialists despite divergent genotypes and morphologies

Expanding the phenotype in argininosuccinic aciduria: need for new therapies

Parallel evolution of gene expression between trophic specialists despite divergent genotypes and morphologies

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