Human Genetics

, Volume 128, Issue 1, pp 79–88 | Cite as

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

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)

References

  1. Aoki Y, Niihori T, Narumi Y, Kure S, Matsubara Y (2008) The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Hum Mutat 29:992–1006CrossRefPubMedGoogle Scholar
  2. Basel-Vanagaite L, Sarig O, Hershkovitz D, Fuchs-Telem D, Rapaport D, Gat A, Isman G, Shirazi I, Shohat M, Enk CD, Birk E, Kohlhase J, Matysiak-Scholze U, Maya I, Knopf C, Peffekoven A, Hennies HC, Bergman R, Horowitz M, Ishida-Yamamoto A, Sprecher E (2009) RIN2 deficiency results in macrocephaly, alopecia, cutis laxa, and scoliosis: MACS syndrome. Am J Hum Genet 85:254–263CrossRefPubMedGoogle Scholar
  3. Carter MS, Doskow J, Morris P, Li S, Nhim RP, Sandstedt S, Wilkinson MF (1995) A regulatory mechanism that detects premature nonsense codons in T-cell receptor transcripts in vivo is reversed by protein synthesis inhibitors in vitro. J Biol Chem 270:28995–29003CrossRefPubMedGoogle Scholar
  4. Fukada T, Civic N, Furuichi T, Shimoda S, Mishima K, Higashiyama H, Idaira Y, Asada Y, Kitamura H, Yamasaki S, Hojyo S, Nakayama M, Ohara O, Koseki H, Dos Santos HG, Bonafe L, Ha-Vinh R, Zankl A, Unger S, Kraenzlin ME, Beckmann JS, Saito I, Rivolta C, Ikegawa S, Superti-Furga A, Hirano T (2008) The zinc transporter SLC39A13/ZIP13 is required for connective tissue development; its involvement in BMP/TGF-beta signaling pathways. PLoS One 3:e3642CrossRefPubMedGoogle Scholar
  5. Giunta C, Elcioglu NH, Albrecht B, Eich G, Chambaz C, Janecke AR, Yeowell H, Weis M, Eyre DR, Kraenzlin M, Steinmann B (2008) Spondylocheiro dysplastic form of the Ehlers–Danlos syndrome—an autosomal-recessive entity caused by mutations in the zinc transporter gene SLC39A13. Am J Hum Genet 82:1290–1305CrossRefPubMedGoogle Scholar
  6. Goloni-Bertollo EM, Ruiz MT, Goloni CB, Muniz MP, Valerio NI, Pavarino-Bertelli EC (2008) GAPO syndrome: three new Brazilian cases, additional osseous manifestations, and review of the literature. Am J Med Genet A 146A:1523–1529CrossRefPubMedGoogle Scholar
  7. Grosshans BL, Ortiz D, Novick P (2006) Rabs and their effectors: achieving specificity in membrane traffic. Proc Natl Acad Sci USA 103:11821–11827CrossRefPubMedGoogle Scholar
  8. Hennies HC, Kornak U, Zhang H, Egerer J, Zhang X, Seifert W, Kuhnisch J, Budde B, Natebus M, Brancati F, Wilcox WR, Muller D, Kaplan PB, Rajab A, Zampino G, Fodale V, Dallapiccola B, Newman W, Metcalfe K, Clayton-Smith J, Tassabehji M, Steinmann B, Barr FA, Nurnberg P, Wieacker P, Mundlos S (2008) Gerodermia osteodysplastica is caused by mutations in SCYL1BP1, a Rab-6 interacting golgin. Nat Genet 40:1410–1412CrossRefPubMedGoogle Scholar
  9. Hucthagowder V, Morava E, Kornak U, Lefeber DJ, Fischer B, Dimopoulou A, Aldinger A, Choi J, Davis EC, Abuelo DN, Adamowicz M, Al-Aama J, Basel-Vanagaite L, Fernandez B, Greally MT, Gillessen-Kaesbach G, Kayserili H, Lemyre E, Tekin M, Turkmen S, Tuysuz B, Yuksel-Konuk B, Mundlos S, Van Maldergem L, Wevers RA, Urban Z (2009) Loss-of-function mutations in ATP6V0A2 impair vesicular trafficking, tropoelastin secretion and cell survival. Hum Mol Genet 18:2149–2165CrossRefPubMedGoogle Scholar
  10. Kimura T, Sakisaka T, Baba T, Yamada T, Takai Y (2006) Involvement of the Ras–Ras-activated Rab5 guanine nucleotide exchange factor RIN2–Rab5 pathway in the hepatocyte growth factor-induced endocytosis of E-cadherin. J Biol Chem 281:10598–10609CrossRefPubMedGoogle Scholar
  11. Kornak U, Reynders E, Dimopoulou A, van Reeuwijk J, Fischer B, Rajab A, Budde B, Nurnberg P, Foulquier F, Lefeber D, Urban Z, Gruenewald S, Annaert W, Brunner HG, van Bokhoven H, Wevers R, Morava E, Matthijs G, Van Maldergem L, Mundlos S (2008) Impaired glycosylation and cutis laxa caused by mutations in the vesicular H+-ATPase subunit ATP6V0A2. Nat Genet 40:32–34CrossRefPubMedGoogle Scholar
  12. Malfait F, De Coster P, Hausser I, van Essen AJ, Franck P, Colige A, Nusgens B, Martens L, De Paepe A (2004) The natural history, including orofacial features of three patients with Ehlers–Danlos syndrome, dermatosparaxis type (EDS type VIIC). Am J Med Genet A 131:18–28CrossRefPubMedGoogle Scholar
  13. Nielsen E, Severin F, Backer JM, Hyman AA, Zerial M (1999) Rab5 regulates motility of early endosomes on microtubules. Nat Cell Biol 1:376–382CrossRefPubMedGoogle Scholar
  14. Nuytinck L, Dalgleish R, Spotila L, Renard JP, Van Regemorter N, De Paepe A (1996) Substitution of glycine-661 by serine in the alpha1(I) and alpha2(I) chains of type I collagen results in different clinical and biochemical phenotypes. Hum Genet 97:324–329CrossRefPubMedGoogle Scholar
  15. Quaglino D Jr, Bergamini G, Boraldi F, Pasquali Ronchetti I (1996) Ultrastructural and morphometrical evaluations on normal human dermal connective tissue—the influence of age, sex and body region. Br J Dermatol 134:1013–1022CrossRefPubMedGoogle Scholar
  16. Saito K, Murai J, Kajiho H, Kontani K, Kurosu H, Katada T (2002) A novel binding protein composed of homophilic tetramer exhibits unique properties for the small GTPase Rab5. J Biol Chem 277:3412–3418CrossRefPubMedGoogle Scholar
  17. Tidyman WE, Rauen KA (2009) The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev 19:230–236CrossRefPubMedGoogle Scholar
  18. Verloes A, Benmansour A, Mortier G, Pierard GE, Le Merrer M (2005) A new recessive connective tissue disorder with fleshy swelling of lips, lid and cheeks, macrocephaly, hyperextensible skin and severe scoliosis. In: 55th annual meeting of the American Society of Human Genetics, vol 674, Salt Lake CityGoogle Scholar
  19. Yeowell HN, Walker LC (2000) Mutations in the lysyl hydroxylase 1 gene that result in enzyme deficiency and the clinical phenotype of Ehlers–Danlos syndrome type VI. Mol Genet Metab 71:212–224CrossRefPubMedGoogle Scholar

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

Personalised recommendations