A novel ARH splice site mutation in a Mexican kindred with autosomal recessive hypercholesterolemia

Canizales‐Quinteros, Samuel; Aguilar-Salinas, Carlos A.; Huertas‐Vazquez, Adriana; Ordóñez-Sánchez, María Luisa; Rodrı́guez-Torres, Maribel; Venturas-Gallegos, José L.; Riba, Laura; Ramírez-Jiménez, Salvador; Salas-Montiel, Rocío; Medina-Palacios, Giovani; Robles‐Osorio, Ludivina; Miliar-García, Ángel; Rosales-León, Luis; Ruíz-Ordaz, Blanca H.; Zentella‐Dehesa, Alejandro; Ferré-D′Amaré, A.R.; Gómez-Pérez, Francisco J.; Tusié-Luna, Ma. Teresa

doi:10.1007/s00439-004-1192-9

Cited by 17 publications

(7 citation statements)

References 35 publications

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“…Xanthomatosis is rarely observed in young children, and when present, homozygous familial hypercholesterolemia (FH) or autosomal recessive hypercholesterolemia is most often suspected 37 38) . Xanthomas may begin to appear at very young age in sitosterolemia, sometimes during the first year of life 33 35) .…”

Section: Clinical Spectrum Of Sitosterolemiamentioning

confidence: 99%

Sitosterolemia: a review and update of pathophysiology, clinical spectrum, diagnosis, and management

Yoo

2016

Ann Pediatr Endocrinol Metab

126

112

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Sitosterolemia is an autosomal recessive disorder characterized by increased plant sterol levels, xanthomas, and accelerated atherosclerosis. Although it was originally reported in patients with normolipemic xanthomas, severe hypercholesterolemia have been reported in patients with sitosterolemia, especially in children. Sitosterolemia is caused by increased intestinal absorption and decreased biliary excretion of sterols resulting from biallelic mutations in either ABCG5 or ABCG8, which encode the sterol efflux transporter ABCG5 and ABCG8. Patients with sitosterolemia show extreme phenotypic heterogeneity, ranging from almost asymptomatic individuals to those with severe hypercholesterolemia leading to accelerated atherosclerosis and premature cardiac death. Hematologic manifestations include hemolytic anemia with stomatocytosis, macrothrombocytopenia, splenomegaly, and abnormal bleeding. The mainstay of therapy includes dietary restriction of both cholesterol and plant sterols and the sterol absorption inhibitor, ezetimibe. Foods rich in plant sterols include vegetable oils, wheat germs, nuts, seeds, avocado, shortening, margarine and chocolate. Hypercholesterolemia in patients with sitosterolemia is dramatically responsive to low cholesterol diet and bile acid sequestrants. Plant sterol assay should be performed in patients with normocholesterolemic xanthomas, hypercholesterolemia with unexpectedly good response to dietary modifications or to cholesterol absorption inhibitors, or hypercholesterolemia with poor response to statins, or those with unexplained hemolytic anemia and macrothrombocytopenia. Because prognosis can be improved by proper management, it is important to find these patients out and diagnose correctly. This review article aimed to summarize recent publications on sitosterolemia, and to suggest clinical indications for plant sterol assay.

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Section: Clinical Spectrum Of Sitosterolemiamentioning

confidence: 99%

Sitosterolemia: a review and update of pathophysiology, clinical spectrum, diagnosis, and management

Yoo

2016

Ann Pediatr Endocrinol Metab

126

112

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“…Recently, the mutation (T56M) of ARH has been associated with hypercholesterolemia (33). Thus far, this is the only point mutation identified on the PTB domain of ARH, but no effect on its binding to LDLR could be detected in a pull-down assay (34). We studied the binding of the LDLR peptide by the corresponding rARH mutant (T55M) in comparison with WT rARH by SPR.…”

Section: Hypercholesterolemia-causing Mutations Destabilize the Arh-ldlrmentioning

confidence: 99%

Atomic structure of the autosomal recessive hypercholesterolemia phosphotyrosine-binding domain in complex with the LDL-receptor tail

Dvir

Shah

Gottardi

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Hypercholesterolemia, high serum cholesterol in the form of LDL, is a major risk factor for atherosclerosis. LDL is mostly degraded in the liver after its cellular internalization with the LDL receptor (LDLR). This clathrin-mediated endocytosis depends on the protein autosomal recessive hypercholesterolemia (ARH), which binds the LDLR cytoplasmic tail. Mutations in either the LDLR tail or in ARH lead to hypercholesterolemia and premature atherosclerosis. Despite the significance of this interaction for cholesterol homeostasis, no structure of either ARH or the LDLR tail is available to determine its molecular basis. We report the crystal structure at 1.37-Å resolution of the phosphotyrosine-binding (PTB) domain of ARH in complex with an LDLR tail peptide containing the FxNPxY 0 internalization signal. Surprisingly, ARH interacts with a longer portion of the tail than previously recognized, which extends to I -7 xF -5 xNPxY 0 QK +2 . The LDLR tail assumes a unique "Hook"-like structure with a double β-turn conformation, which is accommodated in distinctive ARH structural determinants (i.e., an extended backbone hydrogen-bonding platform, three hydrophobic helical grooves, and a hydrophobic pocket for Y 0 ). This unique complementarity differs significantly in related PTB proteins and may account for the unique physiological role of these partners in the hepatic uptake of cholesterol LDL. Moreover, the unusual hydrophobic pocket for Y 0 explains the distinctive ability of ARH to internalize proteins containing either FxNPxY 0 or FxNPxF 0 sequences. Biophysical measurements reveal how mutations associated with hypercholesterolemia destabilize ARH and its complex with LDLR and illuminate LDL internalization defects seen in patients.lipoprotein | crystallography | trafficking | lipid metabolism

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“…Canizales-Quinteros et al (37) reported the characteristics of two Mexican siblings who were found to have a novel splice site mutation at the 1p35 locus (IVS4+2T>G) of the LDLRAP gene. LDLRAP encodes a protein required for clathrin-mediated internalization of the LDLR in the liver.…”

Section: Genetics Of Fh In Latin Americamentioning

confidence: 99%

The panorama of familial hypercholesterolemia in Latin America: a systematic review

Mehta

Zubirán

Martagón

et al. 2016

Journal of Lipid Research

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penetrance. Autosomal dominant FH is attributed to mutations in three different genes: LDL receptor (LDLR), APOB, and proprotein convertase subtilisin/kexin type 9 (PCSK9) (1,(3)(4)(5). Other FH genes have been searched for using exome sequencing without success (2). FH caused by mutations in LDLR adaptor protein (LDLRAP) is known as autosomal recessive FH (2). FH is the most common monogenic disorder leading to premature CHD; despite this fact, it is notoriously underdiagnosed and undertreated worldwide (6).Homozygous FH (HoFH) is characterized by extremely high levels of LDL-C (460-1,160 mg/dl) and early onset coronary artery disease (typically by the second decade of life) (7). Mean LDL-C concentration in untreated patients is close to 615 mg/dl (7,8). Patients are classified into two groups based on the level of LDLR activity, either <2% (receptor negative) or 2-25% (receptor defective). Receptor defective patients have a better prognosis than receptor negative cases (9-11).Heterozygous FH (HeFH) is caused by a single inherited copy of a mutation. The frequency of a heterozygous mutation is >90, 5, and <1% in the LDLR, APOB, and PCSK9 genes, respectively (5). A causal mutation in one of these genes is identified in 60-80% of cases. Affected individuals are characterized by LDL-C levels two to three times greater than normal (190-400 mg/dl). The mean untreated LDL-C concentration is 199.9 mg/dl (12). HeFH is suspected

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A novel ARH splice site mutation in a Mexican kindred with autosomal recessive hypercholesterolemia

Cited by 17 publications

References 35 publications

Sitosterolemia: a review and update of pathophysiology, clinical spectrum, diagnosis, and management

Sitosterolemia: a review and update of pathophysiology, clinical spectrum, diagnosis, and management

Atomic structure of the autosomal recessive hypercholesterolemia phosphotyrosine-binding domain in complex with the LDL-receptor tail

The panorama of familial hypercholesterolemia in Latin America: a systematic review

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