Human Genetics

, Volume 128, Issue 1, pp 79–88

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

  • Delfien Syx
  • Fransiska Malfait
  • Lut Van Laer
  • Jan Hellemans
  • Trinh Hermanns-Lê
  • Andy Willaert
  • Abdelmajid Benmansour
  • Anne De Paepe
  • Alain Verloes
Original Investigation

DOI: 10.1007/s00439-010-0829-0

Cite this article as:
Syx, D., Malfait, F., Van Laer, L. et al. Hum Genet (2010) 128: 79. doi:10.1007/s00439-010-0829-0

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.

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

Supplementary material

439_2010_829_MOESM1_ESM.doc (2.5 mb)
Supplementary material 1 (DOC 2587 kb)

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Delfien Syx
    • 1
  • Fransiska Malfait
    • 1
  • Lut Van Laer
    • 1
  • Jan Hellemans
    • 1
  • Trinh Hermanns-Lê
    • 2
  • Andy Willaert
    • 1
  • Abdelmajid Benmansour
    • 3
  • Anne De Paepe
    • 1
  • Alain Verloes
    • 4
  1. 1.Center for Medical GeneticsGhent University HospitalGhentBelgium
  2. 2.Department of DermatopathologyUniversity Hospital of Sart-TilmanLiègeBelgium
  3. 3.OranAlgeria
  4. 4.Department of GeneticsAP-HP Robert Debré University Hospital and INSERM U676ParisFrance