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The RIN2 syndrome: a new autosomal recessive connective tissue disorder caused by deficiency of Ras and Rab interactor 2 (RIN2)

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Abstract

Defects leading to impaired intracellular trafficking have recently been shown to play an important role in the pathogenesis of genodermatoses, such as the Ehlers–Danlos and the cutis laxa syndromes. A new genodermatosis, termed macrocephaly, alopecia, cutis laxa and scoliosis (MACS) syndrome has been described, resulting from a homozygous 1-bp deletion in RIN2. RIN2 encodes the Ras and Rab interactor 2, involved in the regulation of Rab5-mediated early endocytosis. We performed a clinical, ultrastructural and molecular study in a consanguineous Algerian family with three siblings affected by a distinctive autosomal recessive genodermatosis, reported in 2005 by Verloes et al. The most striking clinical features include progressive facial coarsening, gingival hypertrophy, severe scoliosis, sparse hair and skin and joint hyperlaxity. Ultrastructural studies of the skin revealed important abnormalities in the collagen fibril morphology, and fibroblasts exhibited a dilated endoplasmic reticulum and an abnormal Golgi apparatus with rarefied and dilated cisternae. Molecular analysis of RIN2 revealed a novel homozygous 2-bp deletion in all affected individuals. The c.1914_1915delGC mutation introduces a frameshift and creates a premature termination codon, leading to nonsense-mediated mRNA decay. These findings confirm that RIN2 defects are associated with a distinct genodermatosis and underscore the involvement of RIN2 and its associated pathways in the pathogenesis of connective tissue disorders. The current family displays considerable phenotypic overlap with MACS syndrome. However, our family shows a dermatological and ultrastructural phenotype belonging to the Ehlers–Danlos rather than the cutis laxa spectrum. Therefore, the MACS acronym is not entirely appropriate for the current family.

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Abbreviations

EDS:

Ehlers–Danlos syndrome

GO:

Gerodermia osteodysplastica

MACS:

Macrocephaly, alopecia, cutis laxa and scoliosis

RIN2:

Ras and Rab interactor 2

GEF:

Guanine nucleotide exchange factor

Array-CGH:

Array comparative genome hybridization

BW:

Birth weight

BL:

Birth length

OFC:

Occipitofrontal circumferences

ER:

Endoplasmic reticulum

NMD:

Nonsense-mediated RNA decay

CHX:

Cycloheximide

HCTD:

Heritable connective tissue disorders

GAPO:

Growth retardation, alopecia, pseudo-anodontia and optic atrophy

GTP:

Guanosine triphosphate

GDP:

Guanosine diphosphate

HGF:

Hepatocyte growth factor

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Acknowledgments

We would like to thank Wim Annaert for helpful comments. DS, FM and JH are fellows of the Fund for Scientific Research (FWO), Flanders (Belgium). This work was supported by Methusalem grant 08/01M01108 from the Ghent University to A. De Paepe and grant G.0171.05 from the Fund for Scientific Research, Flanders to A. De Paepe. The experiments comply with the current Belgian laws. This study has been approved by the Ethics Committee of the Ghent University Hospital, Ghent, Belgium.

Conflicts of interest statement

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Center for Medical Genetics, Ghent University Hospital, 9000, Ghent, Belgium

    Delfien Syx, Fransiska Malfait, Lut Van Laer, Jan Hellemans, Andy Willaert & Anne De Paepe

  2. Department of Dermatopathology, University Hospital of Sart-Tilman, Liège, Belgium

    Trinh Hermanns-Lê

  3. Oran, Algeria

    Abdelmajid Benmansour

  4. Department of Genetics, AP-HP Robert Debré University Hospital and INSERM U676, Paris, France

    Alain Verloes

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  1. Delfien Syx
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  2. Fransiska Malfait
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  9. Alain Verloes
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Correspondence to Fransiska Malfait.

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Syx, D., Malfait, F., Van Laer, L. et al. The RIN2 syndrome: a new autosomal recessive connective tissue disorder caused by deficiency of Ras and Rab interactor 2 (RIN2). Hum Genet 128, 79–88 (2010). https://doi.org/10.1007/s00439-010-0829-0

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  • DOI: https://doi.org/10.1007/s00439-010-0829-0

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