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.

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

“…In patient 1, the IEF was slightly abnormal. 28 Ophthalmologic evaluation Patients 2-8 had corneal clouding and/or cataract; patients 4, 7, 9, 10, 12, 13, 14 and 15 had strabismus. …”

“…25 MACS syndrome, caused by mutations in the RIN2 gene is a disorder with very characteristic, discriminatory facial features with sagging chin and severe developmental delay. [26][27][28] Several other syndromes are described in which CL is an associated feature. Intriguing examples are the syndromes caused by genetic alterations in the RAS-MAPK pathway.…”

Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type

“…RIN2 encodes the Ras and Rab interactor-2, which acts as a guanine nucleotide exchange factor for the small GTPase Rab5, which is involved in early endocytosis. 38,39 …”

MACS syndrome: A combined collagen and elastin disorder due to abnormal Golgi trafficking

“…Syx et al [2010] reported patients originating from a consanguineous, Algerian family, presenting with a distinct autosomal recessive genodermatosis. The patients were diagnosed with a novel, 2 bp (c.1914_1915delGC) deletion in RIN2, resulting in nonsense-mediated mRNA decay.…”