RIN2 Deficiency Results in Macrocephaly, Alopecia, Cutis Laxa, and Scoliosis: MACS Syndrome

Basel‐Vanagaite, Lina; Sarig, Ofer; Hershkovitz, Dov; Fuchs-Telem, Dana; Rapaport, David; Gat, Andrea; Isman, Gila; Shirazi, Idit; Shohat, Mordechai; Enk, Claes D.; Birk, Efrat; Kohlhase, Jürgen; Matysiak-Scholze, Uta; Maya, Idit; Knopf, Carlos; Peffekoven, Anette; Hennies, Hans-Christian; Bergman, Reuven; Horowitz, Mia; Ishida‐Yamamoto, Akemi; Sprecher, Eli

doi:10.1016/j.ajhg.2009.07.001

Cited by 86 publications

(85 citation statements)

References 41 publications

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“…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.…”

Section: Introductionmentioning

confidence: 99%

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

et al. 2013

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Patients with cutis laxa (CL) have wrinkled, sagging skin with decreased elasticity. Skin symptoms are associated with variable systemic involvement. The most common, genetically highly heterogeneous form of autosomal recessive CL, ARCL2, is frequently associated with variable metabolic and neurological symptoms. Progeroid symptoms, dysmorphic features, hypotonia and psychomotor retardation are highly overlapping in the early phase of these disorders. This makes the genetic diagnosis often challenging. In search for discriminatory symptoms, we prospectively evaluated clinical, neurologic, metabolic and genetic features in our patient cohort referred for suspected ARCL. From a cohort of 26 children, we confirmed mutations in genes associated with ARCL in 16 children (14 probands), including 12 novel mutations. Abnormal glycosylation and gyration abnormalities were mostly, but not always associated with ATP6V0A2 mutations. Epilepsy was most common in ATP6V0A2 defects. Corpus callosum dysgenesis was associated with PYCR1 and ALDH18A1 mutations. Dystonic posturing was discriminatory for PYCR1 and ALDH18A1 defects. Metabolic markers of mitochondrial dysfunction were found in one patient with PYCR1 mutations. So far unreported white matter abnormalities were found associated with GORAB and RIN2 mutations. We describe a large cohort of CL patients with neurologic involvement. Migration defects and corpus callosum hypoplasia were not always diagnostic for a specific genetic defect in CL. All patients with ATP6V0A2 defects had abnormal glycosylation. To conclude, central nervous system and metabolic abnormalities were discriminatory in this genetically heterogeneous group, although not always diagnostic for a certain genetic defect in CL.

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Section: Introductionmentioning

confidence: 99%

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

et al. 2013

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“…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 …”

Section: Newly Recognized Rare Eds Variantsmentioning

confidence: 99%

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

Malfait

Wenstrup

Paepe

2010

Genetics in Medicine

253

240

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“…This subtype is characterized by fine skin wrinkles, downslanting palpebral fissures, delayed fontanel closure and variable cortical brain anomalies [5,6]. MACS syndrome (Macrocephaly, Alopecia, Cutis laxa, and Scoliosis; OMIM 613075) is secondary to mutations in RIN2 encoding a component of the endosomal compartment which Molecular Genetics and Metabolism 112 (2014) [310][311][312][313][314][315][316] interacts with the small GTPase RAB5 [7]. Gerodermia osteodysplastica (GO; OMIM 231070), due to mutations in the GORAB gene, shows relatively mild cutis laxa, but a prematurely aged aspect and severe osteoporosis.…”

Section: Introductionmentioning

confidence: 99%

Severe congenital cutis laxa with cardiovascular manifestations due to homozygous deletions in ALDH18A1

Fischer

Callewaert

Schröter

et al. 2014

Molecular Genetics and Metabolism

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Autosomal recessive cutis laxa (ARCL) type 2 constitutes a heterogeneous group of diseases mainly characterized by lax and wrinkled skin, skeletal anomalies, and a variable degree of intellectual disability. ALDH18A1-related ARCL is the most severe form within this disease spectrum. Here we report on the clinical and molecular findings of two affected individuals from two unrelated families. The patients presented with typical features of de Barsy syndrome and an overall progeroid appearance. However, the phenotype was highly variable including cardiovascular involvement in the more severe case. Investigation of a skin biopsy of one patient revealed not only the typical alterations of elastic fibers, but also an altered structure of mitochondria in cutaneous fibroblasts. Using conventional sequencing and copy number analysis we identified a frameshift deletion of one nucleotide and a microdeletion affecting the ALDH18A1 gene, respectively, in a homozygous state in both patients. Expression analysis in dermal fibroblasts from the patient carrying the microdeletion showed an almost complete absence of the ALDH18A1 mRNA resulting in an absence of the ALDH18A1 protein. So far, only 13 affected individuals from seven unrelated families suffering from ALDH18A1-related cutis laxa have been described in literature. Our findings provide new insights into the clinical spectrum and show that beside point mutations microdeletions are a possible cause of ALDH18A1-ARCL.

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RIN2 Deficiency Results in Macrocephaly, Alopecia, Cutis Laxa, and Scoliosis: MACS Syndrome

Cited by 86 publications

References 41 publications

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

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

Severe congenital cutis laxa with cardiovascular manifestations due to homozygous deletions in ALDH18A1

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