title: The RIN2 syndrome: a new autosomal recessive connective tissue disorder caused by deficiency of Ras and Rab interactor 2 (RIN2).
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.
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, 9000, Ghent, Belgium.
authors.forename: Delfien
authors.initials: D
authors.lastname: Syx
authors.forename: Fransiska
authors.initials: F
authors.lastname: Malfait
authors.forename: Lut
authors.initials: L
authors.lastname: Van Laer
authors.forename: Jan
authors.initials: J
authors.lastname: Hellemans
authors.forename: Trinh
authors.initials: T
authors.lastname: Hermanns-Lê
authors.forename: Andy
authors.initials: A
authors.lastname: Willaert
authors.forename: Abdelmajid
authors.initials: A
authors.lastname: Benmansour
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.forename: Alain
authors.initials: A
authors.lastname: Verloes
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D003240:Connective Tissue Diseases / Q000235:genetics*; D003241:Consanguinity; D005260:Female; D005808:Genes, Recessive; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D012600:Scoliosis / Q000235:genetics; D015595:Skin Aging; D012871:Skin Diseases / Q000235:genetics*; D013577:Syndrome
chemical_list: D002352:Carrier Proteins; D020662:Guanine Nucleotide Exchange Factors; C447829:RIN2 protein, human