Mutations In OCRL Gene Research Articles

Base editing correction of OCRL in Lowe syndrome: ABE-mediated functional rescue in patient-derived fibroblasts.

Lowe syndrome, a rare X-linked multisystem disorder presenting with major abnormalities in the eyes, kidneys, and central nervous system, is caused by mutations in OCRL gene (NG_008638.1). Encoding an inositol polyphosphate 5-phosphatase, OCRL catalyzes the hydrolysis of PI(4,5)P2 into PI4P. There are no effective targeted treatments for Lowe syndrome. Here, we demonstrate a novel gene therapy for Lowe syndrome in patient fibroblasts using an adenine base editor (ABE) that can efficiently correct pathogenic point mutations. We show that ABE8e-NG-based correction of a disease-causing mutation in a Lowe patient-derived fibroblast line containing R844X mutation in OCRL gene, restores OCRL expression at mRNA and protein levels. It also restores cellular abnormalities that are hallmarks of OCRL dysfunction, including defects in ciliogenesis, microtubule anchoring, α-actinin distribution, and F-actin network. The study indicates that ABE-mediated gene therapy is a feasible treatment for Lowe syndrome, laying the foundation for therapeutic application of ABE in the currently incurable disease.

Novel pathogenic OCRL mutations and genotype\u2013phenotype analysis of Chinese children affected by oculocerebrorenal syndrome: two cases and a literature review

BackgroundOculocerebrorenal syndrome of Lowe is a rare X-linked disorder characterized by congenital cataracts, mental retardation, and proximal tubulopathy. This condition is caused by a mutation of OCRL gene (located at chromosome Xq26.1), which encodes an inositol polyphosphate 5-phosphatase.Case presentationWe identified two novel OCRL mutations in two unrelated Chinese boys, each with a severe phenotype of Lowe syndrome. A novel de novo deletion (hemizygous c.659_662delAGGG, p.E220Vfs*29) was present in patient 1 and a novel splicing mutation (hemizygous c.2257-2A > T) that was maternally inherited was present in patient 2. A renal biopsy in patient 2 indicated mild mesangial proliferative glomerulonephritis, mild focal mononuclear cells infiltration, and interstitial focal fibrosis. Moreover, renal expression of OCRL-1 protein in patient 2 was significantly reduced compared to a control patient with thin basement membrane disease.ConclusionsThis study reports two novel OCRL variants associated with severe ocular and neurologic deficiency, despite only mild renal dysfunction. Based on our two patients and a literature review, the genotype–phenotype correlation of OCRL mutations with this severe phenotype of Lowe syndrome suggest a possible clustering of missense, deletion, and nonsense mutations in the 5-phosphatase domain and Rho-GAP domain in the Chinese population.

A Splicing Variant in OCRL Gene Might Explain the Second Case of Lowe Syndrome in Iran

: Lowe syndrome is a condition that primarily affects eyes, brain, and kidneys. This disorder follows X-linked recessive mode of inheritance and it occurs in males mainly. Mutations in OCRL (located at Xq25) gene can cause accumulation of phosphatidylinositol bisphosphate and disturbed actin cytoskeleton remodeling. There are 268 mutations in OCRL gene causing Lowe syndrome or Dent disease 2 in HGMD database, however 10 - 20% of Lowe syndrome suspects remain undiagnosed at molecular level. Here we present a male case of Lowe syndrome with characteristic features. Comprehensive clinical examination and genetic counseling were performed. Sanger sequencing was employed to investigate the possible OCRL mutations and we identified a donor splice site variant (NM-000276: c.2469 + 1G > A) in hemizygous state. This is a pathogenic variant according to the ACMG standards and guidelines and might explain the clinical features of the patient. This result is in accordance with the clinical diagnosis of Lowe syndrome and it is absent from ExAC, 1000 G, Iranome, GME, gnomAD Genome databases of healthy controls. In-silico analysis of this splicing variant revealed that the position is highly conserved between species. Splicing prediction tools predicted some changes in splicing pattern of the OCRL transcript, elimination of some protein features, and malfunctioning the OCRL protein as a consequence of this variant. Accordingly, we proposed the c.2469 + 1G > A variant might explain the clinical features in studied patient and be employed for prenatal diagnosis of Lowe syndrome in the family.

Lowe syndrome – Old and new evidence of secondary mitochondrial dysfunction

The oculocerebrorenal syndrome of Lowe (LS) is a rare, progressive, multisystemic X-linked disorder caused by mutations in OCRL gene. Patients classically present with ocular abnormalities including bilateral congenital cataracts and glaucoma, intellectual delay, severe generalized hypotonia with absent tendon reflexes, and proximal renal tubular dysfunction. Congenital bilateral cataracts and hypotonia are present at birth in almost all patients, while other classical symptoms develop gradually with variable severity. Consequently, differential diagnosis in infant period in these patients can be broad including other rare metabolic and neurologic disorders.Herein we present a 4.5 year old boy with Lowe syndrome caused by mutation of OCRL gene, NM_000276.4:c.643C > T; p.(Gln215*), initially diagnosed as having mitochondriopathy due to alteration of mitochondria on electron microscopic examination in different tissues and decreased values of mitochondrial energy metabolism measurements in muscle. No pathogenic mutations in mitochondrial DNA were found on whole exome sequencing.This patient recall historical hypothesis of secondary mitochondrial dysfunction in Lowe syndrome, that may be caused/intensified by some of disease symptoms.

Lowe syndrome with extremely short stature: growth hormone deficiency may be the pathogeny

Lowe syndrome is an x-linked disorder characterized by congenital cataracts, nervous system abnormalities and renal tubular dysfunction. With the rising number of reported cases, more patients are found to suffer from endocrine abnormalities. Hereby, three Chinese patients with typical symptoms and extremely short stature were described. The OCRL gene was analyzed. A combination of blood biochemistry and radiological examinations were performed. Growth hormone provocation test was taken in one patient. Nucleotide sequence analysis revealed a de novo novel hemizygous mutation (c.2290_2291delinsCT) in exon 21 in an adolescent boy. As indicated by the growth hormone provocation test, the boy had growth hormone deficiency. The other two patients were brothers with extremely short stature, and manifested the same hemizygous mutation (c.2581G > A) in exon 23. It was speculated that the mutation of OCRL gene could lead to deficiency of growth hormone, for which an early growth hormone intervention may be beneficial.

A case of Lowe syndrome (oculocerebrorenal syndrome): Clinical implications and anaesthetic management

Cataract surgery in neonates and infants can be quite challenging, as many of these children may be having congenital anomalies like Downs, infections like rubella etc. LOWE syndrome is one of the few conditions where the child is born with cataract. LOWE syndrome is a rare X- linked disorder characterised by congenital cataract, mental retardation and Fanconies syndrome. The disease is caused by the mutations of OCRL gene which encodes phospatydyl inositol (4, 5) biphosphatase (Ptdlns (4, 5) P2 phosphatase), protein. We report here the perioperative management of a child with LOWE syndrome who was operated for congenital cataract.

Mutations in OCRL1 gene in Indian children with Lowe syndrome

Lowe syndrome is an X-linked disorder secondary to mutations involving the OCRL1 gene. There are no data on the spectrum of the disease in the Asian population. Detailed clinical assessment, a laboratory assessment which included both glomerular and tubular function tests and genomic DNA analysis, was carried out in six unrelated patients with Lowe syndrome. Analysis of this gene in six unrelated patients with Lowe syndrome showed novel mutations in four and previously described mutations in two. These included a missense mutation (exon 10), two nonsense mutations (exons 10 and 21), two frameshift mutations (exons 12 and 21) and a mutation at the acceptor site of intron 22. The mothers were found to be heterozygote carriers in four cases. This is the first report of mutations involving the OCRL1 gene in patients with Lowe syndrome of Indian origin. These observations have implications for genetic counseling and prenatal diagnosis for families with Lowe syndrome.

A novel interstitial deletion in Xq25, identified by array-CGH in a patient with Lowe syndrome

The oculocerebrorenal syndrome of Lowe (OCRL) (MIM:309000) is an X-linked multisystemic disorder affecting the eyes, nervous system and kidneys due to mutations in OCRL1 gene. The gene contains 24 exons, and encodes a 105 kDa phosphatydylinositol 4,5-biphosphate [PtdIns(4,5)P 2] 5-phosphatase localized primarily in the trans-Golgi network and the lysosomes. The large majority of the OCRL1 mutations producing Lowe syndrome are either missense mutations localized mainly in the catalytic domain or non-sense/frameshift mutations resulting in truncated proteins. Rarely, in about 6% of the cases, the disease results from large gene deletions occurring in the 5′ part of the gene. Here we report a new case of a patient with Lowe syndrome due to a deletion of about 4 Mb, encompassing the OCRL1 gene, detected by PCR and CGH array. The mother was carrier of the same deletion.