OCRLMutation analysis in Italian patients with Lowe syndrome

Addis, Maria; Loi, Mario; Lepiani, Carmen; Cau, Milena; Melis, Maria Paola

doi:10.1002/humu.9239

Cited by 35 publications

(19 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have previously shown that the ΔE585, I768N, and A797P mutations abolish binding to, and co-localization with APPL1, while retaining binding to Rac and clathrin [11]. Mutant forms of the COOH-terminal region of OCRL harboring the three other mutations, V577E [17], L687P (B. Roa unpublished data, http://research.nhgri.nih.gov/lowe/), and C679W, were tested for protein interactions in GST pulldown assays. None of these mutant proteins bound to APPL1 (Fig.…”

Section: Ocrl Patient Mutations Abolish Binding To Appl1mentioning

confidence: 99%

All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding

McCrea

Paradise

Tomasini

et al. 2008

Biochemical and Biophysical Research Communications

Self Cite

View full text Add to dashboard Cite

Mutations in the inositol 5-phosphatase OCRL are responsible for Lowe syndrome, an X-linked disorder characterized by bilateral cataracts, mental retardation, neonatal hypotonia, and renal Fanconi syndrome, and for Dent disease, another X-linked condition characterized by kidney reabsorption defects. We have previously described an interaction of OCRL with the endocytic adaptor APPL1 that links OCRL to protein networks involved in the disease phenotype. Here we provide new evidence showing that among the interactions which target OCRL to membranes of the endocytic pathway, binding to APPL1 is the only one abolished by all known disease-causing missense mutations in the ASH-RhoGAP domains of the protein. Furthermore, we demonstrate that APPL1 and rab5 independently contribute to recruit OCRL to enlarged endosomes induced by the expression of constitutively active Rab5. Thus, binding to APPL1 helps localize OCRL at specific cellular sites, and disruption of this interaction may play a role in disease.

show abstract

Section: Ocrl Patient Mutations Abolish Binding To Appl1mentioning

confidence: 99%

All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding

McCrea

Paradise

Tomasini

et al. 2008

Biochemical and Biophysical Research Communications

Self Cite

View full text Add to dashboard Cite

show abstract

“…Lowe syndrome is transmitted as an X-linked recessive trait with a high rate of new mutations, which are responsible for about one-third of the cases (Lin et al 1997;Addis et al 2004). However, several females showing the complete typical clinical manifestations of the syndrome have been described (Scholten 1960;Svore et al 1967;Harris et al 1979;Sagel et al 1970;Yamashina 1981;Hodgson et al 1986;Mü ller et al 1991).…”

Section: Introductionmentioning

confidence: 99%

“…The 23 coding exons and their flanking intronic sequences of OCRL1 gene were amplified from genomic DNA using forward and reverse primers designed according to nucleotide sequences (Addis et al 2004). …”

Section: Ocrl1 Sequencingmentioning

confidence: 99%

A locus for familial skewed X chromosome inactivation maps to chromosome Xq25 in a family with a female manifesting Lowe syndrome

et al. 2006

Self Cite

View full text Add to dashboard Cite

In mammals, X-linked gene products can be dosage compensated between males and females by inactivation of one of the two X chromosomes in the developing female embryos. X inactivation choice is usually random in embryo mammals, but several mechanisms can influence the choice determining skewed X inactivation. As a consequence, females heterozygous for X-linked recessive disease can manifest the full phenotype. Herein, we report a family with extremely skewed X inactivation that produced the full phenotype of Lowe syndrome, a recessive X-linked disease, in a female. The X chromosome inactivation studies detected an extremely skewed inactivation pattern with a ratio of 100:0 in the propositus as well as in five out of seven unaffected female relatives in four generations. The OCRL1 ''de novo'' mutation resides in the active paternally inherited X chromosome. X chromosome haplotype analysis suggests the presence of a locus for the familial skewed X inactivation in chromosome Xq25 most likely controlling X chromosome choice in X inactivation or cell proliferation. The description of this case adds Lowe syndrome to the list of X-linked disorders which may manifest the full phenotype in females because of the skewed X inactivation.

show abstract

“…Excepting very few cases, the OCRL mutations associated with Dent disease 2 do not overlap with those causing Lowe syndrome. 10,20,24 Missense mutations occur in the middle region of the gene (exons 9-15), whereas truncating mutations are found exclusively in the first 7 exons; the OCRL mutations associated with Lowe syndrome are located instead in the 3 0 region of the gene (exons [9][10][11][12][13][14][15][16][17][18][19][20][21][22] and involve all three functional OCRL1 domains, whereas frameshift and nonsense mutations cluster in exons [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. The different distribution of OCRL mutations in Dent disease 2 and Lowe syndrome suggests a genotype-phenotype correlation that has yet to be thoroughly explored.…”

Section: Resultsmentioning

confidence: 99%

“…Sequences of all 23 coding exons and the flanking intronic sequence of the human OCRL gene were analyzed according to Addis et al 22 The nomenclature of the mutations is based on the cDNA sequence NM_000276.3.…”

Section: Case Reportmentioning

confidence: 99%

An atypical Dent’s disease phenotype caused by co-inheritance of mutations at CLCN5 and OCRL genes

et al. 2012

Self Cite

View full text Add to dashboard Cite

Dent's disease is an X-linked renal tubulopathy caused by mutations mainly affecting the CLCN5 gene. Defects in the OCRL gene, which is usually mutated in patients with Lowe syndrome, have been shown to lead to a Dent-like phenotype called Dent disease 2. However, about 20% of patients with Dent's disease carry no CLCN5/OCRL mutations. The disease's genetic heterogeneity is accompanied by interfamilial and intrafamilial phenotypic heterogeneity. We report on a case of Dent's disease with a very unusual phenotype (dysmorphic features, ocular abnormalities, growth delay, rickets, mild mental retardation) in which a digenic inheritance was discovered. Two different, novel disease-causing mutations were detected, both inherited from the patient's healthy mother, that is a truncating mutation in the CLCN5 gene (A249fs*20) and a donor splice-site alteration in the OCRL gene (c.388 þ 3A4G). The mRNA analysis of the patient's leukocytes revealed an aberrantly spliced OCRL mRNA caused by in-frame exon 6 skipping, leading to a shorter protein, but keeping intact the central inositol 5-phosphatase domain and the C-terminal side of the ASH-RhoGAP domain. Only wild-type mRNA was observed in the mother's leukocytes due to a completely skewed X inactivation. Our results are the first to reveal the effect of an epistatic second modifier in Dent's disease too, which can modulate its expressivity. We surmise that the severe Dent disease 2 phenotype of our patient might be due to an addictive interaction of the mutations at two different genes.

show abstract

OCRLMutation analysis in Italian patients with Lowe syndrome

Cited by 35 publications

References 16 publications

All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding

All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding

A locus for familial skewed X chromosome inactivation maps to chromosome Xq25 in a family with a female manifesting Lowe syndrome

An atypical Dent’s disease phenotype caused by co-inheritance of mutations at CLCN5 and OCRL genes

Contact Info

Product

Resources

About