Introducing and Reviewing a Novel Mutation of ROBO3 in Horizontal Gaze Palsy with Progressive Scoliosis from a Chinese Family

Xiu, Yanghui; Lü, Zhe; Wang, Danni; Chen, Xuejiao; Huang, Songmu; Pan, Meihua

doi:10.1007/s12031-020-01650-4

Cited by 10 publications

(16 citation statements)

References 22 publications

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“…It should be noted that more than 40 different mutations within ROBO3 were reported associated with HGPPS, including missense, deletion, duplication, nonsense, and splice site mutations. 2 However, the missense genetic variant in rs74787566 have not been shown related to HGPPS in previous researches. To further confirm its association with AIS, SNP genotyping was performed in a cohort of 1140 AIS patients and 1580 controls.…”

Section: Discussionmentioning

confidence: 91%

“…In this study, for the first time, we reported that genetic variant of a SNP (rs74787566) within ROBO3 gene were significantly associated with AIS through exome sequencing. It should be noted that more than 40 different mutations within ROBO3 were reported associated with HGPPS, including missense, deletion, duplication, nonsense, and splice site mutations 2. However, the missense genetic variant in rs74787566 have not been shown related to HGPPS in previous researches.…”

Section: Discussionmentioning

confidence: 93%

“…From the data of Drosophila , zebrafish, and mouse, ROBO3 was proved essential for the guidance of hindbrain axon midline crossing to achieve contralateral motor control and sensory input 3,15. Disruptions of ROBO3 functions could lead to HGPPS manifested as severe restriction of conjugate horizontal eye movement, nystagmus, as well as progressive scoliosis during adolescence 2. Unfortunately, since ROBO3 KO mice were unable to live postnatally, the origin of scoliosis onset in HGPPS patients remains unknown 16,17.…”

Section: Discussionmentioning

confidence: 99%

“…3,15 Disruptions of ROBO3 functions could lead to HGPPS manifested as severe restriction of conjugate horizontal eye movement, nystagmus, as well as progressive scoliosis during adolescence. 2 Unfortunately, since ROBO3 KO mice were unable to live postnatally, the origin of scoliosis onset in HGPPS patients remains unknown. 16,17 However, some studies indicated that axon guidance were associated with the development of scoliosis.…”

Section: Discussionmentioning

confidence: 99%

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Genetic Variant of ROBO3 Gene Is Associated with Adolescent Idiopathic Scoliosis in the Chinese Population

Zhang

Shu

et al. 2022

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Study Design. A case-control association study. Objectives. This study aimed to reveal whether mutations within roundabout receptor 3 (ROBO3) gene were related to adolescent idiopathic scoliosis (AIS) in Chinese Han population and to investigate the functional role of ROBO3 in the pathogenesis and progression of AIS. Summary of Background Data. ROBO3 is essential for the regulation of hindbrain axonal cell migration and midline crossing. Studies have demonstrated that ROBO3 homozygous mutations are associated with horizontal gaze palsy with progressive scoliosis. However, whether and how ROBO3 contributed to the development of scoliosis remains unclear. Materials and Methods. Whole exome sequencing was performed in 135 AIS patients and 267 healthy controls to evaluate the differences of single nucleotide polymorphism variants within ROBO3. Then the identified variant of ROBO3 was genotyped in another cohort included 1140 AIS patients and 1580 controls. Moreover, paraspinal muscles were collected from 39 AIS patients and 45 lumbar disk herniation patients for the measurement of ROBO3 mRNA expression. The χ2 test, Fisher exact test or the Student t test were used to compare intergroup data. Pearson correlation was used to determine the association between ROBO3 expression and clinical phenotypes. Results. A significant association was identified between the gene variant (rs74787566) of ROBO3 and the development of AIS through exome sequencing. The genotyping cohort demonstrated a higher frequency of allele A in AIS patients compared to controls (7.89% vs. 4.30%, P<0.001, odds ratio=1.87). In addition, the expression of ROBO3 in paraspinal muscles was inversely correlated with the Cobb angle (P=0.043, r 2=0.1059). Conclusion. A significant association was identified between the gene variant (rs74787566) of ROBO3 and the development of AIS. The reduced expression of ROBO3 could result in the progression of curve magnitude in patients with AIS. Further studies are needed to verify the functional role of ROBO3 in the development of AIS. Level of Evidence. Level III.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Genetic Variant of ROBO3 Gene Is Associated with Adolescent Idiopathic Scoliosis in the Chinese Population

Zhang

Shu

et al. 2022

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“…To date, 76 different mutations, including missense, nonsense, frameshift, splicing, gross deletion, small deletion, small insertion, and small indel mutations, and 174 variants have been reported according to the mastermind database. 31 The most common mutations are missense mutations c.955G > A (p.E319K) and c.2108G > C (p.R703P). 26 HGPPS-related mutations occur in all ROBO3 gene exons and exon-intron boundaries, mostly located on the extracellular part of the protein, inherited both in affected members of consanguineous families harboring homozygous ROBO3 mutations and in individuals from non-consanguineous families harboring compound heterozygous mutations.…”

Section: Discussionmentioning

confidence: 99%

Compound Heterozygous ROBO3 Mutation in Two Siblings Presenting with Horizontal Gaze Palsy without Scoliosis: Case-Based Review

et al. 2021

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Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare, autosomal recessively inherited disorder characterized by a congenital absence of conjugated horizontal eye movements with progressive scoliosis developing in childhood and adolescence. HGPPS is caused by mutations of the ROBO3 gene that disrupts the midline crossing of the descending corticospinal and ascending lemniscal sensory tracts in the medulla. We present two siblings, 5-year-old and 2-year-old boys with HGPPS, from non-consanguineous parents. The older brother was brought for the evaluation of moderate psychomotor retardation. He had bilateral horizontal gaze palsy with preserved vertical gaze and convergence. Scoliosis was absent. Cranial MRI showed brainstem abnormalities, and diffusion tensor imaging showed absent decussation of cortico-spinal tracts in the medulla. Clinical diagnosis of HGPPS was confirmed by sequencing of ROBO3 gene, IVS4–1G > A (c.767–1G > A) and c.328_329delinsCCC (p.Asp110Profs*57) compound heterozygous variations were found, and segregated in parents. The younger boy was first reported at 16 months of age and had the same clinical and neuroradiological findings, unlike mild psychomotor retardation. ROBO3 gene analysis showed the same variants in his brother. Our cases show the importance of evaluating eye movements in children with neurodevelopmental abnormalities and looking for brainstem abnormalities in children with bilateral horizontal gaze palsy.

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Early onset horizontal gaze palsy and progressive scoliosis due to a noncanonical splicing‐site variant and a missense variant in the ROBO3 gene

Qin

Zhou

et al. 2023

Molec Gen & Gen Med

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BackgroundHomozygous or compound heterozygous ROBO3 gene mutations cause horizontal gaze palsy with progressive scoliosis (HGPPS). This is an autosomal recessive disorder that is characterized by congenital absence or severe restriction of horizontal gaze and progressive scoliosis. To date, almost 100 patients with HGPPS have been reported and 55 ROBO3 mutations have been identified.MethodsWe described an HGPPS patient and performed whole‐exome sequencing (WES) to identify the causative gene.ResultsWe identified a missense variant and a splice‐site variant in the ROBO3 gene in the proband. Sanger sequencing of cDNA revealed the presence of an aberrant transcript with retention of 700 bp from intron 17, which was caused by a variation in the noncanonical splicing site. We identified five additional ROBO3 variants, which were likely pathogenic, and estimated the overall allele frequency in the southern Chinese population to be 9.44 × 10−4, by a review of our in‐house database.ConclusionThis study has broadened the mutation spectrum of the ROBO3 gene and has expanded our knowledge of variants in noncanonical splicing sites. The results could help to provide more accurate genetic counseling to affected families and prospective couples. We suggest that the ROBO3 gene should be included in the local screening strategy.

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Introducing and Reviewing a Novel Mutation of ROBO3 in Horizontal Gaze Palsy with Progressive Scoliosis from a Chinese Family

Cited by 10 publications

References 22 publications

Genetic Variant of ROBO3 Gene Is Associated with Adolescent Idiopathic Scoliosis in the Chinese Population

Genetic Variant of ROBO3 Gene Is Associated with Adolescent Idiopathic Scoliosis in the Chinese Population

Compound Heterozygous ROBO3 Mutation in Two Siblings Presenting with Horizontal Gaze Palsy without Scoliosis: Case-Based Review

Early onset horizontal gaze palsy and progressive scoliosis due to a noncanonical splicing‐site variant and a missense variant in the ROBO3 gene

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