Autosomal recessive SLC30A9 variants in a Proband with a Cerebro-Renal Syndrome and No Parental Consanguinity

Kleyner, Robert; Arif, Muhammad; Marchi, Elaine; Horowitz, N.; Haworth, Andrea; King, Brian; Amble, Karen; Gavin, Maureen; Velinov, Milen; Lyon, Gholson J.

doi:10.1101/mcs.a006137

Cited by 6 publications

(16 citation statements)

References 25 publications

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“…Only 1 of our probands (F2) has definite renal dysfunction, although 1 member of family F1 is also known to renal services, and none currently have hypertension or hyperkalemia. Hearing impairment was not found in any of Perez et al's index kindred 2 but was found in the Kleyner et al proband,3 and in at least 3 of the individuals we report here (F1(II-1), F2, and F4): family 3 has not had a detailed audiologic assessment.SLC30A9 encodes ZnT-9, a ubiquitously expressed transmembrane protein, which is known to play a role as a zinc transporter. Perez et al, in the same study in which they report on the disease, offer immunofluorescence-based evidence that the protein colocalizes with cytosolic vesicles and especially the endoplasmic reticulum.…”

contrasting

confidence: 45%

“…Only one of our probands (F2) has definite renal dysfunction, although one member of Family F1 is also known to renal services, and none currently have hypertension or hyperkalaemia. w P ' index kindred (2) but was found in the Kleyner et al proband (3), and in at least three of the individuals we report here (F1(II-1), F2 and F4): Family 3 has not had a detailed audiological assessment.…”

Section: Discussionmentioning

confidence: 62%

“…Upper limb dystonia presented by around age 5 years and progressed to become generalized. Oculomotor apraxia and ptosis, however, were not seen 3. The affected individuals in the additional families we report share the distinctive features of a progressive dyskinetic/dystonic movement disorder, intellectual disability, oculomotor apraxia, and ptosis.…”

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confidence: 54%

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confidence: 99%

“…2 A single individual from a second family with compound heterozygous variants has also very recently been reported. 3 This condition has been designated Birk-Landau-Perez syndrome (BLPS). 4 We describe 4 further families with different biallelic SLC30A9 variants associated with this distinctive clinical syndrome and prominent progressive hyperkinetic movement disorder.…”

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confidence: 99%

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Clinical Phenotype in Individuals With Birk-Landau-Perez Syndrome Associated With Biallelic SLC30A9 Pathogenic Variants

et al. 2023

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Objective: Birk-Landau-Perez syndrome is a genetic disorder caused by biallelic pathogenic variants in SLC30A9 presenting with a complex movement disorder, developmental regression, oculomotor abnormalities and renal impairment. So far it has been reported in only two families. We describe the clinical phenotype of eight further individuals from four unrelated families with SLC30A9-related disease. Method: Following detailed clinical phenotyping, one family underwent research wholegenome sequencing (WGS), one research whole-exome sequencing (WES) and two diagnostic WGS. Variants of interest were assessed for pathogenicity using in silico prediction tools, homology modelling and where relevant, sequencing of cDNA for splicing impact. Results: In two unrelated families of Pakistani origin (one consanguineous, one not), the same homozygous missense variant in SLC30A9 (c.1253G>T, p.Gly418Val) was identified. Family 1 included two affected brothers, and Family 2 one affected boy. In Family 3, also consanguineous, there were four affected siblings homozygous for the variant c.1049delCAG, pAla350del. The fourth family was non-consanguineous: the one affected individual was compound heterozygous for c.1083dup, p.Val362Cysfs*5 and c.1413A>G, p.Ser471=. Despite phenotypic variability between the four families, all affected patients manifested with a progressive hyperkinetic movement disorder, associated with oculomotor apraxia and ptosis. None had evidence of severe renal impairment. For the novel missense variant, the conformation of the loop domain and packing of transmembrane helices are likely to be disrupted based on structure modelling. Its presence in two unrelated Pakistani families suggests a possible founder variant. For the synonymous variant p.Ser471=, an impact on splicing was confirmed through cDNA analysis. Discussion: Pathogenic variants in SLC30A9 cause a progressive autosomal recessive neurological syndrome associated with a complex hyperkinetic movement disorder. Our report highlights the expanding disease phenotype, which can present with a wider spectrum of severity than has previously been recognised.

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confidence: 45%

Section: Discussionmentioning

confidence: 62%

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confidence: 54%

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confidence: 99%

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confidence: 99%

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Clinical Phenotype in Individuals With Birk-Landau-Perez Syndrome Associated With Biallelic SLC30A9 Pathogenic Variants

et al. 2023

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Evaluating the regulatory function of non‐coding autism‐associated single nucleotide polymorphisms on gene expression in human brain tissue

Pugsley,

Namipashaki,

Bellgrove

et al. 2024

Autism Research

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Common variants account for most of the estimated heritability associated with autism spectrum disorder (autism). Although several replicable single nucleotide polymorphisms (SNPs) for the condition have been detected using genome‐wide association study (GWAS) methodologies, their pathophysiological relevance remains elusive. Examining this is complicated, however, as all detected loci are situated within non‐coding regions of the genome. It is therefore likely that they possess roles of regulatory function as opposed to directly affecting gene coding sequences. To bridge the gap between SNP discovery and mechanistic insight, we applied a comprehensive bioinformatic pipeline to functionally annotate autism‐associated polymorphisms and their non‐coding linkage disequilibrium (i.e., non‐randomly associated) partners. We identified 82 DNA variants of probable regulatory function that may contribute to autism pathogenesis. To validate these predictions, we measured the impact of 11 high‐confidence candidates and their GWAS linkage disequilibrium partners on gene expression in human brain tissue from Autistic and non‐Autistic donors. Although a small number of the surveyed variants exhibited measurable influence on gene expression as determined via quantitative polymerase chain reaction, these did not survive correction for multiple comparisons. Additionally, no significant genotype‐by‐diagnosis effects were observed for any of the SNP‐gene associations. We contend that this may reflect an inability to effectively capture the modest, neurodevelopmental‐specific impact of individual variants on biological dysregulation in available post‐mortem tissue samples, as well as limitations in the existing autism GWAS data.

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SLC30A9: an evolutionarily conserved mitochondrial zinc transporter essential for mammalian early embryonic development

Ge,

Li,

Liang

et al. 2024

Cell. Mol. Life Sci.

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SLC30A9 (ZnT9) is a mitochondria-resident zinc transporter. Mutations in SLC30A9 have been reported in human patients with a novel cerebro-renal syndrome. Here, we show that ZnT9 is an evolutionarily highly conserved protein, with many regions extremely preserved among evolutionarily distant organisms. In Drosophila melanogaster (the fly), ZnT9 (ZnT49B) knockdown results in acutely impaired movement and drastic mitochondrial deformation. Severe Drosophila ZnT9 (dZnT9) reduction and ZnT9-null mutant flies are pupal lethal. The phenotype of dZnT9 knockdown can be partially rescued by mouse ZnT9 expression or zinc chelator TPEN, indicating the defect of dZnT9 loss is indeed a result of zinc dyshomeostasis. Interestingly, in the mouse, germline loss of Znt9 produces even more extreme phenotypes: the mutant embryos exhibit midgestational lethality with severe development abnormalities. Targeted mutagenesis of Znt9 in the mouse brain leads to serious dwarfism and physical incapacitation, followed by death shortly. Strikingly, the GH/IGF-1 signals are almost non-existent in these tissue-specific knockout mice, consistent with the medical finding in some human patients with severe mitochondrial deficiecny. ZnT9 mutations cause mitochondrial zinc dyshomeostasis, and we demonstrate mechanistically that mitochondrial zinc elevation quickly and potently inhibits the activities of respiration complexes. These results reveal the critical role of ZnT9 and mitochondrial zinc homeostasis in mammalian development. Based on our functional analyses, we finally discussed the possible nature of the so far identified human SLC30A9 mutations.

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Autosomal recessive SLC30A9 variants in a Proband with a Cerebro-Renal Syndrome and No Parental Consanguinity

Cited by 6 publications

References 25 publications

Clinical Phenotype in Individuals With Birk-Landau-Perez Syndrome Associated With Biallelic SLC30A9 Pathogenic Variants

Clinical Phenotype in Individuals With Birk-Landau-Perez Syndrome Associated With Biallelic SLC30A9 Pathogenic Variants

Evaluating the regulatory function of non‐coding autism‐associated single nucleotide polymorphisms on gene expression in human brain tissue

SLC30A9: an evolutionarily conserved mitochondrial zinc transporter essential for mammalian early embryonic development

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