NDD-linked mutations in genes encoding axonal transport machineries
| Protein . | Gene with mutation . | Inheritance . | Disease: Phenotypes . | References . |
|---|---|---|---|---|
| Microtubules | ||||
| α1A-tubulin | TUBA1A | AD: Missense/insertion/deletion mutations | LIS3: Congenital microcephaly, mental retardation, no language development | Fallet-Bianco et al., 2014; Poirier et al., 2013 |
| β2A-tubulin Class IIa | TUBB2A | AD: Missense mutations | CDCBM5: Intellectual disability, hypotonia, developmental delay, epilepsy | Cushion et al., 2014; Rodan et al., 2017; Schmidt et al., 2021 |
| β-tubulin Class I | TUBB | AD: Missense mutations | CDCBM6: Delayed psychomotor development and microcephaly | Breuss et al., 2012 |
| β2B-tubulin Class IIb | TUBB2B | AD: Missense mutations | CDCBM7: Microcephaly, mental retardation, severe neuromotor impairment, no visual contact, infantile seizures | Cederquist et al., 2012; Laquerriere et al., 2016 |
| β3-tubulin Class III | TUBB3 | AD: Missense mutations | CDCBM1: Mental retardation, strabismus, axial hypotonia, and spasticity | Fallet-Bianco et al., 2014; Poirier et al., 2010 |
| β6-tubulin Class V | TUBB6 | AD: Missense mutations | FPVEPD: Bilateral ptosis and facial palsy, severe rhinophonia aperta with speech articulation defects | Fazeli et al., 2017 |
| γ1-tubulin | TUBG1 | AD: Missense mutations | CDCBM4: Complex cortical malformations, intellectual disability | Poirier et al., 2013 |
| Motor proteins | ||||
| Kinesin-1 | KIF5A | AD: Missense mutations in tail domain | NEIMY: Myoclonic seizures, lack of developmental progress | Duis et al., 2016; Rydzanicz et al., 2017 |
| AD: Missense mutations in motor/stalk/tail domain | SPG 10: Limb spasticity and weakness, sensorimotor polyneuropathy, cognitive impairment | de Boer et al., 2021; de Souza et al., 2017; Méreaux et al., 2022 | ||
| AD: Missense mutations in stalk domain | CMT2: Chronic axonal motor and sensory polyneuropathy | de Boer et al., 2021 | ||
| KIF5B | AR: Missense mutations | Developmental and speech delay | Charng et al., 2016 | |
| KIF5C | AD: Missense mutations in motor domain | CDCBM2: Microcephaly, developed clonic seizures, severe intellectual disability | de Ligt et al., 2012; Poirier et al., 2013 | |
| Kinesin-2 | KIF3B | AD: Missense mutations in motor domain | SZ: Cognitive impairment, delusions, hallucinations, disorganized speech and movements | Alsabban et al., 2020 |
| Kinesin-3 | KIF1A | AD: Missense mutations in motor domain | NESCAVS: Global developmental delay, intellectual disabilities, seizures | Lee et al., 2015; Ohba et al., 2015 |
| AD: Missense mutations in motor domain | HSES: Severe brain edema and atrophy, developmental delay, peripheral neuropathy, autonomic dysfunction | Isobe et al., 2022 | ||
| AR: Truncating mutation | HSN2C: Early onset of hereditary sensory neuropathy, distal muscle weakness, slowed speech development | Rivière et al., 2011 | ||
| AD/AR: Missense mutations in motor domain | SPG30: Early childhood onset unsteady spastic gait, hyperreflexia of the lower limbs, learning disabilities | Citterio et al., 2015; Klebe et al., 2012; Nemani et al., 2020; Pennings et al., 2020 | ||
| KIF1Bβ | AD: Missense mutations in motor domain | CMT2A: Chronic axonal motor and sensory polyneuropathy | Xu et al., 2018; Zhao et al., 2001 | |
| Dynein | DYNC1H1 | AD: Missense mutations in motor/tail domain | CDCBM13: Global developmental delay, intellectual disability, seizures | Poirier et al., 2013; Vissers et al., 2010; Willemsen et al., 2012 |
| AD: Missense mutations in tail domain | SMALED1: Early childhood onset of muscle weakness and atrophy | Harms et al., 2012; Tsurusaki et al., 2012 | ||
| Myosin V | MYO5A | AR: Nonsense or truncating mutation | Hindbrain malformation and developmental delay | Charng et al., 2016 |
| Motor adaptors and regulatory proteins | ||||
| Kinesin-binding protein | KIF1BP/KBP | AR: Nonsense mutation | GOSHS: Intellectual disability, microcephaly | Brooks et al., 2005; Drévillon et al., 2013 |
| AR: Truncating mutations | Polymicrogyria: Microcephaly | Valence et al., 2013 | ||
| Bicaudal D2 | BICD2 | AD: Missense mutations | SMALED2A: Early childhood onset of muscle weakness and atrophy | Neveling et al., 2013; Peeters et al., 2013 |
| AD: Missense mutations | SMALED2B: Decreased fetal movements, severe hypotonia, muscle atrophy, and respiratory insufficiency after birth | Koboldt et al., 2018; Ravenscroft et al., 2016; Storbeck et al., 2017 | ||
| Lissencephaly 1 | PAFAH1B1 | AD: Missense or truncating mutations | LIS: Developmental delay, early onset of seizures | Reiner et al., 1993; Saillour et al., 2009 |
| NudE neurodevelopment protein 1 | NDE1 | AR: Truncating or nonsense mutations | LIS4: Severe microcephaly, mental retardation, early-onset epilepsy | Abdel-Hamid et al., 2019; Alkuraya et al., 2011 |
| AR: Nonsense mutation or intragenic deletion | MHAC: Microcephaly, motor and mental retardation | Abdel-Hamid et al., 2019; Guven et al., 2012 | ||
| Syntabulin | SYBU | N/A: Missense mutation | Autism: Delayed or absent language development, learning disability, repetitive speech or motor behaviors, social deficits, seizure | Herman et al., 2016; Xiong et al., 2021 |
| Disrupted in schizophrenia 1 | DISC1 | N/A: Missense mutation | SZ9: Cognitive impairment, delusions, hallucinations, disorganized speech and movements | Schumacher et al., 2009; Song et al., 2008 |
| FMRP | FMR1 | XLD: Missense and truncating mutations, unstable expanded CCG repeat | FXS: Impaired intellectual development, autistic traits, distinct facial features, and seizures | De Boulle et al., 1993; Grønskov et al., 2011; Kremer et al., 1991 |
| CLIPs | CLIP1 | AR | ARID: Intellectual disability | Larti et al., 2015 |
| Protein . | Gene with mutation . | Inheritance . | Disease: Phenotypes . | References . |
|---|---|---|---|---|
| Microtubules | ||||
| α1A-tubulin | TUBA1A | AD: Missense/insertion/deletion mutations | LIS3: Congenital microcephaly, mental retardation, no language development | Fallet-Bianco et al., 2014; Poirier et al., 2013 |
| β2A-tubulin Class IIa | TUBB2A | AD: Missense mutations | CDCBM5: Intellectual disability, hypotonia, developmental delay, epilepsy | Cushion et al., 2014; Rodan et al., 2017; Schmidt et al., 2021 |
| β-tubulin Class I | TUBB | AD: Missense mutations | CDCBM6: Delayed psychomotor development and microcephaly | Breuss et al., 2012 |
| β2B-tubulin Class IIb | TUBB2B | AD: Missense mutations | CDCBM7: Microcephaly, mental retardation, severe neuromotor impairment, no visual contact, infantile seizures | Cederquist et al., 2012; Laquerriere et al., 2016 |
| β3-tubulin Class III | TUBB3 | AD: Missense mutations | CDCBM1: Mental retardation, strabismus, axial hypotonia, and spasticity | Fallet-Bianco et al., 2014; Poirier et al., 2010 |
| β6-tubulin Class V | TUBB6 | AD: Missense mutations | FPVEPD: Bilateral ptosis and facial palsy, severe rhinophonia aperta with speech articulation defects | Fazeli et al., 2017 |
| γ1-tubulin | TUBG1 | AD: Missense mutations | CDCBM4: Complex cortical malformations, intellectual disability | Poirier et al., 2013 |
| Motor proteins | ||||
| Kinesin-1 | KIF5A | AD: Missense mutations in tail domain | NEIMY: Myoclonic seizures, lack of developmental progress | Duis et al., 2016; Rydzanicz et al., 2017 |
| AD: Missense mutations in motor/stalk/tail domain | SPG 10: Limb spasticity and weakness, sensorimotor polyneuropathy, cognitive impairment | de Boer et al., 2021; de Souza et al., 2017; Méreaux et al., 2022 | ||
| AD: Missense mutations in stalk domain | CMT2: Chronic axonal motor and sensory polyneuropathy | de Boer et al., 2021 | ||
| KIF5B | AR: Missense mutations | Developmental and speech delay | Charng et al., 2016 | |
| KIF5C | AD: Missense mutations in motor domain | CDCBM2: Microcephaly, developed clonic seizures, severe intellectual disability | de Ligt et al., 2012; Poirier et al., 2013 | |
| Kinesin-2 | KIF3B | AD: Missense mutations in motor domain | SZ: Cognitive impairment, delusions, hallucinations, disorganized speech and movements | Alsabban et al., 2020 |
| Kinesin-3 | KIF1A | AD: Missense mutations in motor domain | NESCAVS: Global developmental delay, intellectual disabilities, seizures | Lee et al., 2015; Ohba et al., 2015 |
| AD: Missense mutations in motor domain | HSES: Severe brain edema and atrophy, developmental delay, peripheral neuropathy, autonomic dysfunction | Isobe et al., 2022 | ||
| AR: Truncating mutation | HSN2C: Early onset of hereditary sensory neuropathy, distal muscle weakness, slowed speech development | Rivière et al., 2011 | ||
| AD/AR: Missense mutations in motor domain | SPG30: Early childhood onset unsteady spastic gait, hyperreflexia of the lower limbs, learning disabilities | Citterio et al., 2015; Klebe et al., 2012; Nemani et al., 2020; Pennings et al., 2020 | ||
| KIF1Bβ | AD: Missense mutations in motor domain | CMT2A: Chronic axonal motor and sensory polyneuropathy | Xu et al., 2018; Zhao et al., 2001 | |
| Dynein | DYNC1H1 | AD: Missense mutations in motor/tail domain | CDCBM13: Global developmental delay, intellectual disability, seizures | Poirier et al., 2013; Vissers et al., 2010; Willemsen et al., 2012 |
| AD: Missense mutations in tail domain | SMALED1: Early childhood onset of muscle weakness and atrophy | Harms et al., 2012; Tsurusaki et al., 2012 | ||
| Myosin V | MYO5A | AR: Nonsense or truncating mutation | Hindbrain malformation and developmental delay | Charng et al., 2016 |
| Motor adaptors and regulatory proteins | ||||
| Kinesin-binding protein | KIF1BP/KBP | AR: Nonsense mutation | GOSHS: Intellectual disability, microcephaly | Brooks et al., 2005; Drévillon et al., 2013 |
| AR: Truncating mutations | Polymicrogyria: Microcephaly | Valence et al., 2013 | ||
| Bicaudal D2 | BICD2 | AD: Missense mutations | SMALED2A: Early childhood onset of muscle weakness and atrophy | Neveling et al., 2013; Peeters et al., 2013 |
| AD: Missense mutations | SMALED2B: Decreased fetal movements, severe hypotonia, muscle atrophy, and respiratory insufficiency after birth | Koboldt et al., 2018; Ravenscroft et al., 2016; Storbeck et al., 2017 | ||
| Lissencephaly 1 | PAFAH1B1 | AD: Missense or truncating mutations | LIS: Developmental delay, early onset of seizures | Reiner et al., 1993; Saillour et al., 2009 |
| NudE neurodevelopment protein 1 | NDE1 | AR: Truncating or nonsense mutations | LIS4: Severe microcephaly, mental retardation, early-onset epilepsy | Abdel-Hamid et al., 2019; Alkuraya et al., 2011 |
| AR: Nonsense mutation or intragenic deletion | MHAC: Microcephaly, motor and mental retardation | Abdel-Hamid et al., 2019; Guven et al., 2012 | ||
| Syntabulin | SYBU | N/A: Missense mutation | Autism: Delayed or absent language development, learning disability, repetitive speech or motor behaviors, social deficits, seizure | Herman et al., 2016; Xiong et al., 2021 |
| Disrupted in schizophrenia 1 | DISC1 | N/A: Missense mutation | SZ9: Cognitive impairment, delusions, hallucinations, disorganized speech and movements | Schumacher et al., 2009; Song et al., 2008 |
| FMRP | FMR1 | XLD: Missense and truncating mutations, unstable expanded CCG repeat | FXS: Impaired intellectual development, autistic traits, distinct facial features, and seizures | De Boulle et al., 1993; Grønskov et al., 2011; Kremer et al., 1991 |
| CLIPs | CLIP1 | AR | ARID: Intellectual disability | Larti et al., 2015 |
NDD-linked genetic mutations in genes encoding the axonal transport machinery, along with their inheritance patterns and disease phenotypes.
Inheritance: AD, autosomal dominant; AR, autosomal recessive; N/A, not applicable; XLD, X-linked dominant; ARID, autosomal recessive intellectual disability; CDCBM1-13, complex cortical dysplasia with other brain malformations-1-13; CMT2, Charcot-Marie-Tooth disease 2; FPVEPD, facial palsy with ptosis and velopharyngeal dysfunction; FXS, fragile X syndrome; GOSHS, Goldberg-Shprintzen syndrome; HSES, hemorrhagic shock and encephalopathy syndrome; HSN2C, hereditary sensory neuropathy type IIC; IAHSP, infantile-onset ascending hereditary spastic paralysis; LIS, lissencephaly; LIS3, lissencephaly 3; LIS4, lissencephaly 4; MHAC, microhydranencephaly; NEIMY, neonatal intractable myoclonus; NESCAVS, neurodegeneration and spasticity with or without cerebellar atrophy or cortical visual impairment syndrome; SCZD, schizophrenia; SMALED1, lower extremity-predominant spinal muscular atrophy-1; SMALED2A, childhood-onset lower extremity-predominant spinal muscular atrophy-2A; SMALED2B, prenatal-onset lower extremity-predominant spinal muscular atrophy-2B; SPG10, spastic paraplegia type 10; SPG30, spastic paraplegia type 30.