Rett and Rett‐like syndrome: Expanding the genetic spectrum to <i>KIF1A</i> and <i>GRIN1</i> gene

Wang, Jiaping; Zhang, Qingping; Chen, Yan; Yu, Shujie; Wu, Xiru; Bao, Xinhua

doi:10.1002/mgg3.968

Cited by 32 publications

(33 citation statements)

References 56 publications

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“…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). Our in vitro analysis indicates that the p.(Asp248Glu) variant results in a marked decrease in the ability of KIF1A to undergo processive motility to the plus ends of microtubules in the neurite tips of SH‐SY5Y cells and significantly lower velocity of microtubule movement compared with wild‐type KIF1A.…”

Section: Discussionmentioning

confidence: 99%

“…A subset of KIF1A patients shares some clinical features with RTT including gait abnormalities, hypotonia, scoliosis, seizures, and intellectual disability. Recently a de novo heterozygous truncating variant [NM_001244008.1: c.275_276insAA; NP_001230937.1: p.(Cys92*)] in the motor domain of KIF1A has been reported in a single female case presenting with classic RTT including developmental delay, microcephaly, lack of independent ambulation and speech, loss of hand skills, hand clapping and mouthing, bruxism, breathing and sleep disturbances (Wang et al, 2019). Interestingly, the well‐conserved KIF1A motor domain has been identified as a mutation hotspot (with over 80 reported variants) resulting in a spectrum of phenotypes that overlap with other neurological disorders including RTT.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

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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“…Mutations may be present in MECP2 or other related genes including CDKL5, FOXG1, GRIN1 and KIF1A. 5,11 In the present case, we report a girl who showed hyperactive social behavior, fits and seizure, loss of speech abilities, limb weakness, intellectual disability and growth retardation. Her EEG showed abnormal wave discharge confirming epileptic fits and CT-scan showed atrophic changes.…”

Section: Discussionmentioning

confidence: 77%

“…Her EEG showed abnormal wave discharge confirming epileptic fits and CT-scan showed atrophic changes. 5,11 heterogeneity of this disease. In Pakistan, very few reports with Rett syndrome epilepsy have been described.…”

Section: Discussionmentioning

confidence: 99%

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Rett Syndrome without MECP2 Mutation in a Pakistani Girl

Dad¹,

Sawal²,

Ahmad³

et al. 2020

L&S

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Rett syndrome is a rare inherited neurodegenerative disease which mostly affects females but has a lethal impact on males. Rett syndrome is mostly caused by mutations of Methyl CpG binding protein-2 (MECP2) gene located on chromosome Xq28. A 7-year girl from a consanguineous Pakistani family presented with history of abnormal social behavior, tonic colonic seizures, limb'sataxia, intellectual disability, growth retardation and speech abnormalities. Physical and neurological examinations established likely clinical features of Rett syndrome with abnormal electroencephalogram (EEG). Genetic testing of MECP2 gene did not identify any functional nucleotide variation indicating the involvement of another gene mutation in this patient. A consanguineous case of Rett syndrome did not carry the mutation of MECP2 gene. Due to heterogeneity of the phenotype, it is proposed that there might be involvement of another locus for this disease. In future, targeted next generation sequence can be helpful to identify the causative mutation in this patient.A 7-year old girl visited the hospital, with a history of hyperactive behavior, delayed milestones,

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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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Rett and Rett‐like syndrome: Expanding the genetic spectrum to KIF1A and GRIN1 gene

Cited by 32 publications

References 56 publications

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

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

Rett Syndrome without MECP2 Mutation in a Pakistani Girl

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

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