ANK3 related neurodevelopmental disorders: expanding the spectrum of heterozygous loss-of-function variants

AbstractANK3 encodes multiple isoforms of ankyrin-G, resulting in variegated tissue expression and function, especially regarding its role in neuronal development. Based on the zygosity, location, and type, ANK3 variants result in different neurodevelopmental phenotypes. Autism spectrum disorder has been associated with heterozygous missense variants in ANK3, whereas a more severe neurodevelopmental phenotype is caused by isoform-dependent, autosomal-dominant, or autosomal-recessive loss-of-function variants. Here, we present four individuals affected by a variable neurodevelopmental phenotype harboring a heterozygous frameshift or nonsense variant affecting all ANK3 transcripts. Thus, we provide further evidence of an isoform-based phenotypic continuum underlying ANK3-associated pathologies and expand its phenotypic spectrum.

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DJ-1 regulates the integrity and function of ER-mitochondria association through interaction with IP3R3-Grp75-VDAC1

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1906565116 ◽

2019 ◽

Vol 116 (50) ◽

pp. 25322-25328 ◽

Cited By ~ 20

Author(s):

Yi Liu ◽

Xiaopin Ma ◽

Hisashi Fujioka ◽

Jun Liu ◽

Shengdi Chen ◽

...

Keyword(s):

Autosomal Recessive ◽

Cellular Mechanism ◽

Loss Of Function ◽

Wild Type ◽

Calcium Efflux ◽

And Function ◽

The Brain ◽

Early Onset Parkinson’S Disease

Loss-of-function mutations in DJ-1 are associated with autosomal recessive early onset Parkinson’s disease (PD), yet the underlying pathogenic mechanism remains elusive. Here we demonstrate that DJ-1 localized to the mitochondria-associated membrane (MAM) both in vitro and in vivo. In fact, DJ-1 physically interacts with and is an essential component of the IP3R3-Grp75-VDAC1 complexes at MAM. Loss of DJ-1 disrupted the IP3R3-Grp75-VDAC1 complex and led to reduced endoplasmic reticulum (ER)-mitochondria association and disturbed function of MAM and mitochondria in vitro. These deficits could be rescued by wild-type DJ-1 but not by the familial PD-associated L166P mutant which had demonstrated reduced interaction with IP3R3-Grp75. Furthermore, DJ-1 ablation disturbed calcium efflux-induced IP3R3 degradation after carbachol treatment and caused IP3R3 accumulation at the MAM in vitro. Importantly, similar deficits in IP3R3-Grp75-VDAC1 complexes and MAM were found in the brain of DJ-1 knockout mice in vivo. The DJ-1 level was reduced in the substantia nigra of sporadic PD patients, which was associated with reduced IP3R3-DJ-1 interaction and ER-mitochondria association. Together, these findings offer insights into the cellular mechanism in the involvement of DJ-1 in the regulation of the integrity and calcium cross-talk between ER and mitochondria and suggests that impaired ER-mitochondria association could contribute to the pathogenesis of PD.

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Novel COL11A2 Pathogenic Variants in a Child with Autosomal Recessive Otospondylomegaepiphyseal Dysplasia: A Review of the Literature

Journal of Pediatric Genetics ◽

10.1055/s-0039-1698446 ◽

2019 ◽

Vol 09 (02) ◽

pp. 117-120

Author(s):

Pavalan Selvam ◽

Shekhar Singh ◽

Angita Jain ◽

Herjot Atwal ◽

Paldeep S. Atwal

Keyword(s):

Sequence Analysis ◽

Autosomal Recessive ◽

Autosomal Dominant ◽

Review Of The Literature ◽

Pathogenic Variants ◽

Phenotypic Spectrum ◽

Whole Exome ◽

The Family ◽

Type Xi Collagen ◽

Exome Sequence

AbstractOtospondylomegaepiphyseal dysplasia (OSMED) is an inherited autosomal dominant and recessive skeletal dysplasia caused by both heterozygous and homozygous pathogenic variants in COL11A2 encoding the α2(XI) collagen chains, a part of type XI collagen. Here, we describe a 2-year-old girl presenting from birth with a phenotype suggestive of OSMED. On whole exome sequence analysis of the family via commercially available methods, we detected two novel heterozygous pathogenic variants in the proband. In addition, we reviewed the phenotype of autosomal recessive OSMED cases with COL11A2 pathogenic variants reported to date and quantitatively highlighted the phenotypic spectrum.

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TCF12 haploinsufficiency causes autosomal dominant Kallmann syndrome and reveals network-level interactions between causal loci

Human Molecular Genetics ◽

10.1093/hmg/ddaa120 ◽

2020 ◽

Vol 29 (14) ◽

pp. 2435-2450

Author(s):

Erica E Davis ◽

Ravikumar Balasubramanian ◽

Zachary A Kupchinsky ◽

David L Keefe ◽

Lacey Plummer ◽

...

Keyword(s):

Autosomal Recessive ◽

Autosomal Dominant ◽

Kallmann Syndrome ◽

Gonadotropin Releasing Hormone ◽

Loss Of Function ◽

Binding Partner ◽

Zebrafish Larvae ◽

Syndromic Craniosynostosis ◽

Molecular Components

Abstract Dysfunction of the gonadotropin-releasing hormone (GnRH) axis causes a range of reproductive phenotypes resulting from defects in the specification, migration and/or function of GnRH neurons. To identify additional molecular components of this system, we initiated a systematic genetic interrogation of families with isolated GnRH deficiency (IGD). Here, we report 13 families (12 autosomal dominant and one autosomal recessive) with an anosmic form of IGD (Kallmann syndrome) with loss-of-function mutations in TCF12, a locus also known to cause syndromic and non-syndromic craniosynostosis. We show that loss of tcf12 in zebrafish larvae perturbs GnRH neuronal patterning with concomitant attenuation of the orthologous expression of tcf3a/b, encoding a binding partner of TCF12, and stub1, a gene that is both mutated in other syndromic forms of IGD and maps to a TCF12 affinity network. Finally, we report that restored STUB1 mRNA rescues loss of tcf12 in vivo. Our data extend the mutational landscape of IGD, highlight the genetic links between craniofacial patterning and GnRH dysfunction and begin to assemble the functional network that regulates the development of the GnRH axis.

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A de novo STUB1 variant associated with an early adult-onset multisystemic ataxia phenotype

Journal of Neurology ◽

10.1007/s00415-021-10524-7 ◽

2021 ◽

Author(s):

David Mengel ◽

Andreas Traschütz ◽

Selina Reich ◽

Alejandra Leyva-Gutiérrez ◽

Friedemann Bender ◽

...

Keyword(s):

Early Onset ◽

Autosomal Recessive ◽

Autosomal Dominant ◽

De Novo ◽

Family Members ◽

Start Codon ◽

Mrna Levels ◽

Adult Onset ◽

Loss Of Function ◽

Autosomal Dominant Disorder

Abstract Background Biallelic STUB1 variants are a well-established cause of autosomal-recessive early-onset multisystemic ataxia (SCAR16). Evidence for STUB1 variants causing autosomal-dominant ataxia (SCA48) so far largely relies on segregation data in larger families. Presenting the first de novo occurrence of a heterozygous STUB1 variant, we here present additional qualitative evidence for STUB1-disease as an autosomal-dominant disorder. Methods Whole exome sequencing on an index patient with sporadic early-onset ataxia, followed by Sanger sequencing in all family members, was used to identify causative variants as well as to rule out alternative genetic hits and intronic STUB1 variants. STUB1 mRNA and protein levels in PBMCs in all family members were analysed using qRT-PCR and Western Blot. Results A previously unreported start-lost loss-of-function variant c.3G>A in the start codon of STUB1 was identified in the index case, occurring de novo and without evidence for a second (potentially missed) variant (e.g., intronic or copy number) in STUB1. The patient showed an early adult-onset multisystemic ataxia complicated by spastic gait disorder, distal myoclonus and cognitive dysfunction, thus closely mirroring the systems affected in autosomal-recessive STUB1-associated disease. In line with the predicted start-lost effect of the variant, functional investigations demonstrated markedly reduced STUB1 protein expression in PBMCs, whereas mRNA levels were intact. Conclusion De novo occurrence of the loss-of-function STUB1 variant in our case with multisystemic ataxia provides a qualitatively additional line of evidence for STUB1-disease as an autosomal-dominant disorder, in which the same neurological systems are affected as in its autosomal-recessive counterpart. Moreover, this finding adds support for loss-of-function as a mechanism underlying autosomal-dominant STUB1-disease, thus mirroring its autosomal-recessive counterpart also in terms of the underlying mutational mechanism.

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The Analysis of Variants in the General Population Reveals That PMM2 Is Extremely Tolerant to Missense Mutations and That Diagnosis of PMM2-CDG Can Benefit from the Identification of Modifiers

International Journal of Molecular Sciences ◽

10.3390/ijms19082218 ◽

2018 ◽

Vol 19 (8) ◽

pp. 2218 ◽

Cited By ~ 16

Author(s):

Valentina Citro ◽

Chiara Cimmaruta ◽

Maria Monticelli ◽

Guglielmo Riccio ◽

Bruno Hay Mele ◽

...

Keyword(s):

General Population ◽

Autosomal Recessive ◽

Biochemical Analysis ◽

Autosomal Recessive Disease ◽

Type I ◽

Missense Mutations ◽

Loss Of Function ◽

Phenotype Correlation ◽

Phenotypic Spectrum ◽

Partial Deficiency

Type I disorders of glycosylation (CDG), the most frequent of which is phosphomannomutase 2 (PMM2-CDG), are a group of diseases causing the incomplete N-glycosylation of proteins. PMM2-CDG is an autosomal recessive disease with a large phenotypic spectrum, and is associated with mutations in the PMM2 gene. The biochemical analysis of mutants does not allow a precise genotype–phenotype correlation for PMM2-CDG. PMM2 is very tolerant to missense and loss of function mutations, suggesting that a partial deficiency of activity might be beneficial under certain circumstances. The patient phenotype might be influenced by variants in other genes associated with the type I disorders of glycosylation in the general population.

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Prevalence and Phenotypic Spectrum of PINK1 Mutations in Parkinson’s Disease

US Neurology ◽

10.17925/usn.2009.05.01.34 ◽

2009 ◽

Vol 05 (01) ◽

pp. 34 ◽

Cited By ~ 1

Author(s):

Alessandro Ferraris ◽

Enza Maria Valente ◽

Anna Rita Bentivoglio ◽

◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Autosomal Recessive ◽

Autosomal Dominant ◽

Clinical Presentation ◽

Rare Variants ◽

Age At Onset ◽

Early Age ◽

Slow Disease Progression ◽

Phenotypic Spectrum

Several genes have been identified as causative of autosomal dominant or recessive forms of Parkinson’s disease (PD). Bi-allelic mutations in the PTEN-induced putative kinase 1 (PINK1) gene represent the second most frequent cause of autosomal recessive parkinsonism (ARP) after PARK2/Parkin. The typicalPINK1-associated phenotype is characterized by early age at onset, slow disease progression, and excellent and sustained response to levodopa, but in rare cases the clinical presentation can be indistinguishable from that of sporadic PD. Single heterozygous rare variants in thePINK1gene, as well as in other ARP genes, have been frequently detected both in parkinsonian patients and in healthy controls. Although their pathogenetic role is still debated, these variants have been suggested to act as minor risk factors for developing PD.

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Congenital macrothrombocytopenia with focal myelofibrosis due to mutations in human G6b-B is rescued in humanized mice

Blood ◽

10.1182/blood-2017-08-802769 ◽

2018 ◽

Vol 132 (13) ◽

pp. 1399-1412 ◽

Cited By ~ 14

Author(s):

Inga Hofmann ◽

Mitchell J. Geer ◽

Timo Vögtle ◽

Andrew Crispin ◽

Dean R. Campagna ◽

...

Keyword(s):

Autosomal Recessive ◽

Humanized Mice ◽

Loss Of Function ◽

Physiological Functions ◽

Platelet Production ◽

Key Points ◽

And Function

Key Points Autosomal recessive loss-of-function mutations in G6b-B (MPIG6B) cause congenital macrothrombocytopenia with focal myelofibrosis. G6b-B has orthologous physiological functions in human and mice regulating megakaryocyte and platelet production and function.

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Proteins linked to autosomal dominant and autosomal recessive disorders harbor characteristic rare missense mutation distribution patterns

10.1101/018648 ◽

2015 ◽

Author(s):

Tychele Turner ◽

Christopher Douville ◽

Dewey Kim ◽

Peter D Stenson ◽

David N Cooper ◽

...

Keyword(s):

Missense Mutation ◽

Autosomal Recessive ◽

Autosomal Dominant ◽

Distribution Patterns ◽

Missense Mutations ◽

Loss Of Function ◽

Gain Of Function ◽

Disease Etiology ◽

Missense Variants ◽

Significant Difference

The role of rare missense variants in disease causation remains difficult to interpret. We explore whether the clustering pattern of rare missense variants (MAF<0.01) in a protein is associated with mode of inheritance. Mutations in genes associated with autosomal dominant (AD) conditions are known to result in either loss or gain of function, whereas mutations in genes associated with autosomal recessive (AR) conditions invariably result in loss of function. Loss- of-function mutations tend to be distributed uniformly along protein sequence, while gain-of- function mutations tend to localize to key regions. It has not previously been ascertained whether these patterns hold in general for rare missense mutations. We consider the extent to which rare missense variants are located within annotated protein domains and whether they form clusters, using a new unbiased method called CLUstering by Mutation Position (CLUMP). These approaches quantified a significant difference in clustering between AD and AR diseases. Proteins linked to AD diseases exhibited more clustering of rare missense mutations than those linked to AR diseases (Wilcoxon P=5.7x10-4, permutation P=8.4x10-4). Rare missense mutation in proteins linked to either AD or AR diseases were more clustered than controls (1000G) (Wilcoxon P=2.8x10-15 for AD and P=4.5x10-4 for AR, permutation P=3.1x10-12 for AD and P=0.03 for AR). Differences in clustering patterns persisted even after removal of the most prominent genes. Testing for such non-random patterns may reveal novel aspects of disease etiology in large sample studies.

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Novel loss-of-function variants in TRIO are associated with neurodevelopmental disorder: case report

BMC Medical Genetics ◽

10.1186/s12881-020-01159-y ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Laura Schultz-Rogers ◽

Karthik Muthusamy ◽

Filippo Pinto e Vairo ◽

Eric W. Klee ◽

Brendan Lanpher

Keyword(s):

Developmental Delays ◽

Autosomal Dominant ◽

Neurodevelopmental Disorder ◽

Loss Of Function ◽

Dominant Inheritance ◽

Case Presentation ◽

The Third ◽

Phenotypic Spectrum ◽

Missense Variation ◽

Cutis Aplasia

Abstract Background Damaging variants in TRIO have been associated with moderate to severe neurodevelopmental disorders in humans. While recent work has delineated the positional effect of missense variation on the resulting phenotype, the clinical spectrum associated with loss-of-function variation has yet to be fully defined. Case presentation We report on two probands with novel loss-of-function variants in TRIO. Patient 1 presents with a severe neurodevelopmental disorder and macrocephaly. The TRIO variant is inherited from his affected mother. Patient 2 presents with moderate developmental delays, microcephaly, and cutis aplasia with a frameshift variant of unknown inheritance. Conclusions We describe two patients with neurodevelopmental disorder, macro/microcephaly, and cutis aplasia in one patient. Both patients have loss-of-function variants, helping to further characterize how these types of variants affect the phenotypic spectrum associated with TRIO. We also present the third reported case of autosomal dominant inheritance of a damaging variant in TRIO.

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Biallelic Loss-of-Function Variants in AIMP1 Cause a Rare Neurodegenerative Disease

Journal of Child Neurology ◽

10.1177/0883073818811223 ◽

2018 ◽

Vol 34 (2) ◽

pp. 74-80 ◽

Cited By ~ 3

Author(s):

Andrea Accogli ◽

Kether Guerrero ◽

Maria Daniela D’Agostino ◽

Luan Tran ◽

Cécile Cieuta-Walti ◽

...

Keyword(s):

Neuronal Development ◽

Neurodegenerative Disorder ◽

Cerebral Atrophy ◽

Trna Synthetase ◽

Homozygous Mutation ◽

Missense Mutations ◽

Loss Of Function ◽

Pathogenic Variants ◽

The Central Nervous System ◽

And Function

AIMP1/p43, is a noncatalytic component of the mammalian multi-tRNA synthetase complex that catalyzes the ligation of amino acids to their cognate tRNAs. AIMP1 is largely expressed in the central nervous system, where it is part of the regulatory machine of the neurofilament assembly, playing a crucial role in neuronal development and function. To date, nonsense mutations in AIMP1 have been associated with a primary neurodegenerative disorder consisting of cerebral atrophy, hypomyelination, microcephaly and epilepsy, whereas missense mutations have recently been linked to intellectual disability without neurodegeneration. Here, we report the first French-Canadian patient with a novel frameshift AIMP1 homozygous mutation (c.191_192delAA, p.Gln64Argfs*25), resulting in a severe neurodegenerative phenotype. We review and discuss the phenotypic spectrum associated with AIMP1 pathogenic variants.

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