Elaborating the phenotypic spectrum associated with mutations in ARFGEF2: Case study and literature review

doi:10.1016/j.ejpn.2013.05.002

European Journal of Paediatric Neurology

Volume 17, Issue 6, November 2013, Pages 666-670

https://doi.org/10.1016/j.ejpn.2013.05.002 Get rights and content

Abstract

Background

The BIG2 protein, coded by ARFGEF2 indirectly assists neuronal proliferation and migration during cortical development. Mutations in ARFGEF2 have been reported as a rare cause of periventricular heterotopia.

Methods

The presence of periventricular heterotopia, acquired microcephaly and suspected recessive inheritance led to mutation analysis of ARFGEF2 in two affected siblings and their healthy consanguineous parents, after mutations in FLNA had been ruled out.

Results

A homozygous c.242_249delins7 (p.Pro81fs) mutation in exon 3 of ARFGEF2 was identified in the siblings. The alteration is a combination of 2 missense mutations (c.242C > A and c.247G > T) and a frameshift mutation (c.249delA) resulting in a premature stop codon. The clinical phenotype was characterized by dystonic quadriplegia, marked developmental delay, obstructive cardiomyopathy, recurrent infections and feeding difficulties. Degenerative features included early regression, acquired microcephaly and cerebral atrophy. Brain MRI revealed bilateral periventricular heterotopia, small corpus callosum, cerebral and hippocampal atrophy and hyperintensity in the putamen.

Conclusion

Mutations in ARFGEF2 can be anticipated based on characteristic clinical and imaging features.

Introduction

Homeostasis of the Golgi apparatus should be preserved for regulation of complex vesicular networks, their target destination and the proteins in the lipid bilayer. In eukaryotes, this is mostly mediated by a small G protein called ADP-ribosylation factor 1 (ARF1). Its inhibition has been previously shown to completely disassemble the Golgi apparatus.1, 2 Arf1 is necessary for vesicle budding and recruitment of coat complexes to the plasma membrane.3, 4 Arf1 molecules are activated through GTP-GDP exchange which is mediated by a subfamily of proteins called the BIG/Sec7 Arf 1 GEFs. These carry out their function via their Sec7 domain, which shows high homology among the family members.³ Two of these proteins, BIG1 (NP_006412) and BIG2 (NP_006411), encoded in humans by the ARFGEF1 (NM_006421.4) and ARFGEF2 (NM_006420.2) genes respectively, are responsible for interior membrane trafficking in the trans-Golgi network and endosomes.³ Mutations in ARFGEF2 have been reported to cause Autosomal Recessive Periventricular Heterotopia with Microcephaly (ARPHM) in two consanguineous Turkish pedigrees; one with a non-synonymous c.625G > A substitution in exon 6 and the other with a complex mutation of c.242C > A, c.247G > T and c.249delA in exon 3.⁵ Clinical features included microcephaly, severe developmental delay with no postural acquisition, quadriparesis, and poor eye contact, as well as early-onset refractory epilepsy, and recurrent infections.5, 6 A second report described a patient of Dutch origin with delayed developmental milestones, spastic paraplegia with axial hypotonia, chorea, and dystonia, due to compound heterozygosity for the c.2031_2038dup and c.3798_3802del mutations.⁷ We report another consanguineous family of Turkish origin with 3 affected children homozygous for the mutation reported by Sheen et al.

Section snippets

Materials and methods

Following a negative search for mutations in the X-linked FLNA gene (NM_001110556.1) which represent the most frequent genetic cause of bilateral periventricular heterotopia, using conditions described previously,⁸ the proband was then tested for mutations in ARFGEF2 (RefSeq NM_006420.2) in the Department of Clinical Genetics, Erasmus Medical Center, Rotterdam and the Laboratoire Maladies Rares in Bordeaux, France. Targeted mutation analysis was then performed in the proband's sister and both

Case study

The proband (Fig. 1A, II.1) was born at 37 weeks gestation without any complications. Head circumference at birth was 36 cm. The family history was positive for epilepsy and mental retardation in a maternal aunt (Fig. 1A, I.1). A younger brother (Fig. 1A, II.3) had mild developmental delay. At age 3 months, a severe obstructive cardiomyopathy was detected, which prompted administration of propranolol with positive response. At age 8 months, he had marked axial hypotonia and absent head control.

Discussion

The clinical phenotype associated with mutations in ARFGEF2 is relatively homogeneous in the families reported so far (Table 1). It is characterized by normal or near to normal presentation at birth, followed by a degenerative course with axial hypotonia, developmental delay, acquired microcephaly and brain atrophy on MRI. Given the acquired microcephaly, it is likely that cerebral atrophy develops over time. Unfortunately, the progressive loss of cerebral volume could not be documented in the

Conflict of interest

The authors declare no conflict of interest.

Acknowledgments

The authors acknowledge the family for their collaboration. IT is funded by a grant from UZOR (UZ Brussel Onderzoeksraad). AJ received support from the Scientific Fund Willy Gepts.

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Malformations of cortical development (MCD) are a phenotypically and genetically heterogeneous group of disorders, for which the diagnostic rate of genetic testing in a clinical setting remains to be clarified. In this study we aimed to assess the diagnostic rate of germline and pathogenic variants using a custom panel in a heterogeneous group of subjects with MCD and explore genotype-phenotype correlations.
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Customized gene panels may support the diagnostic work-up for some specific MCD, especially when these are diffuse, bilateral and associated with other brain malformations.
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Mutations in FLNA are associated with high prenatal lethality in males. If present in combination with severe microcephaly and even more in the case of familial consanguinity, bi-allelic mutations in ARFGEF2 should be ruled out (Tanyalcin et al., 2013). Periventricular heterotopia with overlying polymicrogyria, especially in the presence of syndactyly, is highly suggestive for heterozygous mutations in NEDD4L (Broix et al., 2016; Kato et al., 2017).
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Mutations in ADP-ribosylation factor guanine nucleotide-exchange factor 2 (ARFGEF2) gene was recently recognized to cause bilateral periventricular nodular heterotopia, putaminal hyperintensity and movement disorder.
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Case studyElaborating the phenotypic spectrum associated with mutations in ARFGEF2: Case study and literature review

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

Materials and methods

Case study

Discussion

Conflict of interest

Acknowledgments

Meth Enzymol

J Biol Chem

Cell

insights into the control of membrane traffic and organelle structure

J Cell Biol

Mechanisms of transport through the Golgi complex

J Cell Sci

Large Arf1 guanine nucleotide exchange factors: evolution, domain structure, and roles in membrane trafficking and human disease

Mol Genet Genomics

Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex

Nat Genet

Case study
Elaborating the phenotypic spectrum associated with mutations in ARFGEF2: Case study and literature review