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

Albrecht, Beate; Brouwer, Arjan Pm de; Lefeber, Dirk; Cremer, Kirsten; Haußer, Ingrid; Rossen, N. P.; Wortmann, Saskia B.; Wevers, Ron A.; Kornak, Uwe; Morava, Éva

doi:10.1002/ajmg.a.33712

Cited by 14 publications

(15 citation statements)

References 8 publications

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“…Fibroblasts of the patients reported so far showed abnormal morphology of the Golgi apparatus with swollen cisternae and vacuole accumulation. Biochemical investigations in one of the patients showed normal plasma N-glycans and variable alterations of the mucin type O-glycan Apolipoprotein C-III 1 , similar to the profile seen in patients with abnormal Golgi-related O-glycosylation (Albrecht et al 2010;Wopereis et al 2003Wopereis et al , 2006. Besides their role for endosome function RIN proteins have also been described as a regulator of the Raspathway.…”

Section: Rin2mentioning

confidence: 66%

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Metabolic cutis laxa syndromes

Mohamed

Kouwenberg

Gardeitchik

et al. 2011

J of Inher Metab Disea

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Cutis laxa is a rare skin disorder characterized by wrinkled, redundant, inelastic and sagging skin due to defective synthesis of elastic fibers and other proteins of the extracellular matrix. Wrinkled, inelastic skin occurs in many cases as an acquired condition. Syndromic forms of cutis laxa, however, are caused by diverse genetic defects, mostly coding for structural extracellular matrix proteins. Surprisingly a number of metabolic disorders have been also found to be associated with inherited cutis laxa. Menkes disease was the first metabolic disease reported with old-looking, wrinkled skin. Cutis laxa has recently been found in patients with abnormal glycosylation. The discovery of the COG7 defect in patients with wrinkled, inelastic skin was the first genetic link with the Congenital Disorders of Glycosylation (CDG). Since then several inborn errors of metabolism with cutis laxa have been described with variable severity. These include P5CS, ATP6V0A2-CDG and PYCR1 defects. In spite of the evolving number of cutis laxa-related diseases a large part of the cases remain genetically unsolved. In metabolic cutis laxa syndromes the clinical and laboratory features might partially overlap, however there are some distinct, discriminative features. In this review on metabolic diseases causing cutis laxa we offer a practical approach for the differential diagnosis of metabolic cutis laxa syndromes.

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Section: Rin2mentioning

confidence: 66%

“…Menkes disease and X-linked cutis laxa have abnormal copper metabolism leading to easily detectable abnormalities in serum and urine but normal TIEF and apoC-III IEF. Patients with RIN2 defect have also normal serum TIEF pattern but have been associated with abnormal O-glycosylation (Albrecht et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Metabolic cutis laxa syndromes

Mohamed

Kouwenberg

Gardeitchik

et al. 2011

J of Inher Metab Disea

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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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“…A mild hypoglycosylation of serum proteins can also be observed in RIN2-related cutis laxa. 16,17 Gerodermia osteodysplastica (GO [MIM: 231070]) is caused by mutations in GORAB (MIM: 607983) encoding an effector of the small GTPases RAB6 and ARF5. 18 Individuals affected by GO have a progeroid aspect, pronounced osteoporosis with fractures in early infancy, and usually no intellectual disability.…”

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confidence: 99%

Recurrent De Novo Mutations Affecting Residue Arg138 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa

Fischer-Zirnsak

Escande‐Beillard

Ganesh

et al. 2015

The American Journal of Human Genetics

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Progeroid disorders overlapping with De Barsy syndrome (DBS) are collectively denoted as autosomal-recessive cutis laxa type 3 (ARCL3). They are caused by biallelic mutations in PYCR1 or ALDH18A1, encoding pyrroline-5-carboxylate reductase 1 and pyrroline-5-carboxylate synthase (P5CS), respectively, which both operate in the mitochondrial proline cycle. We report here on eight unrelated individuals born to non-consanguineous families clinically diagnosed with DBS or wrinkly skin syndrome. We found three heterozygous mutations in ALDH18A1 leading to amino acid substitutions of the same highly conserved residue, Arg138 in P5CS. A de novo origin was confirmed in all six probands for whom parental DNA was available. Using fibroblasts from affected individuals and heterologous overexpression, we found that the P5CS-p.Arg138Trp protein was stable and able to interact with wild-type P5CS but showed an altered sub-mitochondrial distribution. A reduced size upon native gel electrophoresis indicated an alteration of the structure or composition of P5CS mutant complex. Furthermore, we found that the mutant cells had a reduced P5CS enzymatic activity leading to a delayed proline accumulation. In summary, recurrent de novo mutations, affecting the highly conserved residue Arg138 of P5CS, cause an autosomal-dominant form of cutis laxa with progeroid features. Our data provide insights into the etiology of cutis laxa diseases and will have immediate impact on diagnostics and genetic counseling.

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

Cited by 14 publications

References 8 publications

Metabolic cutis laxa syndromes

Metabolic cutis laxa syndromes

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

Recurrent De Novo Mutations Affecting Residue Arg138 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa

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