KIF21A pathogenic variants cause congenital fibrosis of extraocular muscles type 3

Al‐Haddad, Christiane; Boustany, Rose‐Mary; Rachid, Elza; Ismail, Karine; Barry, Brenda; Chan, Wai‐Man; Engle, Elizabeth C.

doi:10.1080/13816810.2020.1852576

Cited by 6 publications

(6 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…KIF21A belongs to the molecular motor kinesin family, comprising an N-terminal motor domain, three central coiled-coil stalk domains, and a C-terminal tail domain containing seven WD40 repeats ( Figure 4 ). To date, at least 15 KIF21A pathogenic variants and related amino acid substitutions accounting for the pathomechanisms have been identified, influencing ocular motor neuron axonal guidance [ 25 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. Remarkably, the majority of these amino acid substitutions were located in the second coiled-coil stalk domain according to UniProt predictions [ 37 ].…”

Section: Geneticsmentioning

confidence: 99%

Congenital Fibrosis of the Extraocular Muscles: An Overview from Genetics to Management

Xia

Wei

et al. 2022

Children

View full text Add to dashboard Cite

Congenital fibrosis of the extraocular muscles (CFEOM) is a genetic disorder belonging to the congenital cranial dysinnervation disorders and is characterized by nonprogressive restrictive ophthalmoplegia. It is phenotypically and genotypically heterogeneous. At least seven causative genes and one locus are responsible for the five subtypes, named CFEOM-1 to CFEOM-5. This review summarizes the currently available molecular genetic findings and genotype–phenotype correlations, as well as the advances in the management of CFEOM. We propose that the classification of the disorder could be optimized to provide better guidance for clinical interventions. Finally, we discuss the future of genetic-diagnosis-directed studies to better understand such axon guidance disorders.

show abstract

Section: Geneticsmentioning

confidence: 99%

Congenital Fibrosis of the Extraocular Muscles: An Overview from Genetics to Management

Xia

Wei

et al. 2022

Children

View full text Add to dashboard Cite

show abstract

“…CFEOM3 is autosomal dominant inherited and is caused by either KIF21A gene mutations [ 9 – 12 ] or three different tubulins: tubulin beta 3 class III ( TUBB3 ) located in chromosome 16q24, tubulin beta 2B class IIb ( TUBB2B ) located in chromosome 6p25, and tubulin alpha 1a ( TUBA1A ) located in chromosome 12q13. Unilateral and asymmetric ptosis and oculomotor defect are often present in individuals with CFEOM3 [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Phenotype, genotype, and management of congenital fibrosis of extraocular muscles type 1 in 16 Chinese families

Chen

Huang

Zhang

et al. 2022

Graefes Arch Clin Exp Ophthalmol

View full text Add to dashboard Cite

Purpose Congenital fibrosis of extraocular muscles type 1 (CFEOM1), a classical subtype of CFEOM, is characterized by restrictive ophthalmoplegia and ptosis. It is mainly caused by aberrant neural innervation of the extraocular muscles. This study aimed to investigate the genetic characteristics and clinical manifestations of CFEOM1 in Chinese families. Methods The clinical data, including ocular examinations, magnetic resonance imaging (MRI), and surgical procedures of affected individuals from 16 Chinese CFEOM1 families, were collected. The genomic DNA of 16 probands and their family members were sequenced for causative KIF21A gene mutations. Linkage analysis using microsatellite markers across KIF21A was also conducted. Results Affected individuals were presented with bilateral non-progressive ptosis, restricted horizontal eye movement, fixed infraduction of both eyes, compensatory chin-up head position, and neuromuscular abnormalities. Three heterozygous KIF21A mutations, c.2860C > T (p.R954W) (in eight families), c.2861G > T (p.R954L) (in two families), and c.2861G > A (p.R954Q) (in two families) were identified, which implied that hotspot mutations were common in Chinese CFEOM1 families. Germline Mosaicism was likely to be the cause of affected individuals with asymptomatic parents without KIF21A mutations presented in the eight families. Two affected individuals underwent modified levator muscle complex suspension surgery and achieved a good result without any complications. Conclusion Instead of evaluating the whole CFEOM1 gene variant, hotspot mutations could be given priority for screening. The occurrence of germline mosaicism has to be taken into account in genetic counseling. Patients with CFEOM1 who have ptosis may benefit from an innovative surgical procedure called modified levator muscle complex suspension.

show abstract

“…An expanding number of mutations in tubulin and the kinesin KIF21A are known to cause congenital fibrosis of the extraocular muscles (CFEOM), an eye-movement disorder caused by impaired axon growth and/or maintenance that prevents the oculomotor nerve from properly innervating ocular muscles Al-Haddad et al, 2020;Traboulsi & Engle, 2004;Ryan & Engle, 2015;. While mutations in the tubulin isotypes TUBB3, TUBB2B or TUBA1A often result in CFEOM accompanied with other neurological developmental disorders , those in KIF21A generally cause isolated CFEOM .…”

Section: Phylogeny Tree Reconstruction and Conservation Profilingmentioning

confidence: 99%

“…CFEOM is a neurodevelopmental eye disease characterized by limited eye movement due to diminished oculomotor axon guidance/maintenance and degeneration of the extraocular muscles. CFEOM-associated mutations have been discovered in the β-tubulins, TUBB3 and TUBB2B, in the α-tubulin, TUBA1A, as well as in the kinesin-4, KIF21A with or without accompanying MCD and intellectual disabilities Al-Haddad et al, 2020;Traboulsi & Engle, 2004;Ryan & Engle, 2015;. Various cellular, biochemical, and animal studies performed to understand the molecular mechanism of CFEOM showed that many β-tubulin CFEOM mutations disrupt kinesin activity .…”

Section: β-Tubulin Cfeom Mutations Can Disrupt or Hyperactivate Kines...mentioning

confidence: 99%

“…One study has demonstrated that engineering a mutation in the L12 loop on kinesin reverses the effect of CFEOM-associated tubulin mutation on kinesin transport disruption and in the CFEOM phenotype in mouse, thereby showing that kinesin disruption is key to CFEOM development . Additionally, variants in kinesin, KIF21A, have also been associated with CFEOM development which hyperactivates kinesin transport (Al-Haddad et al, 2020;van der Vaart et al, 2013;. Thus, disruption and/or hyperactivation of kinesin transport is a likely mechanism for CFEOM formation.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Consequences of pathogenic tubulin-mutations on molecular motor proteins and their implications in tubulinopathies

Sinha Roy

View full text Add to dashboard Cite

First and foremost, I would like to express my deepest gratitude to my mentor, Dr. Mohan Gupta, for his encouragement, motivation, continuous support, and guidance throughout this journey. I grew so much as a scientist over these years with his immense knowledge, mentorship, kindness and patience. He was always around, be it for discussing experiments/results, chatting about exciting advancements in the field, teaching me new techniques, or being my sounding board for career advancements. Thank you, Moe, for being a great mentor and for taking a chance on me.

show abstract

KIF21A pathogenic variants cause congenital fibrosis of extraocular muscles type 3

Cited by 6 publications

References 13 publications

Congenital Fibrosis of the Extraocular Muscles: An Overview from Genetics to Management

Congenital Fibrosis of the Extraocular Muscles: An Overview from Genetics to Management

Phenotype, genotype, and management of congenital fibrosis of extraocular muscles type 1 in 16 Chinese families

Consequences of pathogenic tubulin-mutations on molecular motor proteins and their implications in tubulinopathies

Contact Info

Product

Resources

About