Optic nerve hypoplasia in a patient with a de novo KIF1A heterozygous mutation

Raffa, Lina; Matton, M.; Michaud, Jacques L.; Rossignol, Elsa; Décarie, Jean‐Claude; Ospina, Luis H.

doi:10.1016/j.jcjo.2017.02.021

Cited by 14 publications

(7 citation statements)

References 4 publications

(8 reference statements)

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“…The remaining set of variants have only been reported with CNS involvement; out of these variants causing CNS involvement, the variant associated with the most severe phenotype is p.Glu253Lys-also present in subject BG3associating with severe developmental delay (nonambulatory, nonverbal), optic nerve atrophy, seizures, and cerebellar atrophy (Esmaeeli Nieh et al, 2015;Lee et al, 2015;Muir et al, 2019;Samanta & Gokden, 2019). Thus, there is a striking distinction between variants that tend to cause pure HSP versus those causing the vast majority of HSP cases with CNS involvement, indicative of been reported as causal for both "pure" and "complicated" AD HSP, MRD9, PEHO syndrome, and optic atrophy (Cheon et al, 2017;Esmaeeli Nieh et al, 2015;Lee et al, 2015;Pennings et al, 2020;Raffa et al, 2017;Samanta & Gokden, 2019). Some clinical features are shared between these entities: lower-extremity spasticity, hypotonia, intellectual disability, cerebellar and optic atrophy, hyperreflexia, and convulsion/seizures.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, KIF1A variants have been reported to cause a variety of ‘distinct’ disorders exhibiting significant phenotypic overlap, suggesting a variable spectrum of clinical presentation associating with a common etiology rather than meaningfully distinct clinical diagnoses. For example, KIF1A heterozygous variants have been reported as causal for both “pure” and “complicated” AD HSP, MRD9, PEHO syndrome, and optic atrophy (Cheon et al, 2017; Esmaeeli Nieh et al, 2015; Lee et al, 2015; Pennings et al, 2020; Raffa et al, 2017; Samanta & Gokden, 2019). Some clinical features are shared between these entities: lower‐extremity spasticity, hypotonia, intellectual disability, cerebellar and optic atrophy, hyperreflexia, and convulsion/seizures.…”

Section: Discussionmentioning

confidence: 99%

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Phenotypic expansion in KIF1A ‐related dominant disorders: A description of novel variants and review of published cases

et al. 2020

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KIF1A is a molecular motor for membrane-bound cargo important to the development and survival of sensory neurons. KIF1A dysfunction has been associated with several Mendelian disorders with a spectrum of overlapping phenotypes, ranging from spastic paraplegia to intellectual disability. We present a novel pathogenic inframe deletion in the KIF1A molecular motor domain inherited by two affected siblings from an unaffected mother with apparent germline mosaicism. We identified eight additional cases with heterozygous, pathogenic KIF1A variants ascertained from a local data lake. Our data provide evidence for the expansion of

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Phenotypic expansion in KIF1A ‐related dominant disorders: A description of novel variants and review of published cases

et al. 2020

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“…Characteristic of SPG30, she has progressive lower limb spasticity as well as mild optic nerve atrophy consistent with observations in KIF1A ‐related cases. However, in contrast to KIF1A ‐related disorders, her brain MRI at 12 years of age was normal (Lee et al, 2015; Ohba et al, 2015; Raffa et al, 2017). Recently, a classic RTT female patient was reported carrying a de novo heterozygous nonsense variant p.(Cys92*) in KIF1A with a normal brain MRI (age not specified; Wang et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A ( KIF1A )

et al. 2020

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Defects in the motor domain of kinesin family member 1A (KIF1A), a neuron‐specific ATP‐dependent anterograde axonal transporter of synaptic cargo, are well‐recognized to cause a spectrum of neurological conditions, commonly known as KIF1A‐associated neurological disorders (KAND). Here, we report one mutation‐negative female with classic Rett syndrome (RTT) harboring a de novo heterozygous novel variant [NP_001230937.1:p.(Asp248Glu)] in the highly conserved motor domain of KIF1A. In addition, three individuals with severe neurodevelopmental disorder along with clinical features overlapping with KAND are also reported carrying de novo heterozygous novel [NP_001230937.1:p.(Cys92Arg) and p.(Pro305Leu)] or previously reported [NP_001230937.1:p.(Thr99Met)] variants in KIF1A. In silico tools predicted these variants to be likely pathogenic, and 3D molecular modeling predicted defective ATP hydrolysis and/or microtubule binding. Using the neurite tip accumulation assay, we demonstrated that all novel KIF1A variants significantly reduced the ability of the motor domain of KIF1A to accumulate along the neurite lengths of differentiated SH‐SY5Y cells. In vitro microtubule gliding assays showed significantly reduced velocities for the variant p.(Asp248Glu) and reduced microtubule binding for the p.(Cys92Arg) and p.(Pro305Leu) variants, suggesting a decreased ability of KIF1A to move along microtubules. Thus, this study further expanded the phenotypic characteristics of KAND individuals with pathogenic variants in the KIF1A motor domain to include clinical features commonly seen in RTT individuals.

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“…Structural grading of foveal morphology was performed according to Thomas et al (30). The other family members exhibited normal OCT findings of the optic nerve and macular region ( (8,10,14,16,17,26,(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46) and/or FVH (40,(47)(48)(49)(50)(51).…”

Section: Severe Bilateral Optic Nerve Hypoplasia and Foveal Hypoplasimentioning

confidence: 99%

Atonal homolog 7 (ATOH7) loss-of-function mutations in predominant bilateral optic nerve hypoplasia

Atac

Koller

Hanson

et al. 2019

Human Molecular Genetics

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Optic nerve hypoplasia (ONH) is a congenital optic nerve abnormality caused by underdevelopment of retinal ganglion cells (RGCs). Despite being a rare disease, ONH is the most common optic disc anomaly in ophthalmological practice. So far, mutations in several genes have been identified as causative, however many cases of ONH remain without a molecular explanation. The early transcription factor atonal basic-helix-loop-helix (bHLH) transcription factor 7 (ATOH7) is expressed in retinal progenitor cells and has a crucial role in RGC development. Previous studies have identified several mutations in the ATOH7 locus in cases of eye developmental diseases such as nonsyndromic congenital retinal nonattachment and persistent hyperplasia of the primary vitreous. Here we present two siblings with a phenotype predominated by bilateral ONH, with additional features of foveal hypoplasia and distinct vascular abnormalities, where whole-exome sequencing identified two compound heterozygous missense mutations affecting a conserved amino acid residue within the bHLH domain of ATOH7 (NM_145178.3:c.175G>A; p.(Ala59Thr) and c.176C>T; p.(Ala59Val)). ATOH7 expression constructs with patient single nucleotide variants were cloned for functional characterization. Protein analyses revealed decreased protein amounts and significantly enhanced degradation in the presence of E47, a putative bHLH dimerization partner. Protein interaction assays revealed decreased heterodimerization and DNA-binding of ATOH7 variants, resulting in total loss of transcriptional activation of luciferase reporter gene expression. These findings strongly support pathogenicity of the two ATOH7 mutations, one of which is novel. Additionally, this report highlights the possible impact of altered ATOH7 dimerization on protein stability and function.

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Optic nerve hypoplasia in a patient with a de novo KIF1A heterozygous mutation

Abstract: Fig. 2 -Brain magnetic resonance imaging sagittal and axial views demonstrating global cerebral atrophy with predominant cerebellar atrophy and extremely thinned corpus callosum.

Cited by 14 publications

References 4 publications

Phenotypic expansion in KIF1A ‐related dominant disorders: A description of novel variants and review of published cases

Phenotypic expansion in KIF1A ‐related dominant disorders: A description of novel variants and review of published cases

Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A ( KIF1A )

Atonal homolog 7 (ATOH7) loss-of-function mutations in predominant bilateral optic nerve hypoplasia

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