Two cases of Lowe syndrome caused by a novel mutation in OCRL gene in a family

doi:10.21203/rs.3.rs-4677145/v1

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Case Report

Two cases of Lowe syndrome caused by a novel mutation in OCRL gene in a family

https://doi.org/10.21203/rs.3.rs-4677145/v1

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Background

Lowe syndrome is a rare X-linked recessive genetic disease characterized by congenital binocular cataracts, central nervous system developmental delay, and progressive renal failure caused by tubular injury. Mutations in the OCRL gene can lead to two diseases: Dent-2 syndrome and Lowe syndrome.

Case introduction: Two boys from a family have similar clinical manifestations, including congenital bilateral cataracts, mild developmental abnormalities, and low molecular weight proteinuria. Through whole exome sequencing, it was found that both boys had missense mutations on exon 21 (c.2302A > T, p.Ile768Phe), a newly discovered mutation site.

Conclusion

The discovery of Lowe syndrome in a family of children should be taken seriously, and genetic validation should be conducted on the remaining children in the family as soon as possible. Early intervention and treatment of the disease should be carried out to delay the progression.(This case report is a retrospective study. The parents of the patient have signed an informed consent form and agreed to publish the report. The clinical trial has not been registered.)

Lowe syndrome

OCRL gene

Genetic mutations

Clinical phenotype

Lowe syndrome is a rare X-linked recessive genetic disease with an incidence rate of about 1/500000, is mostly seen in male patients. The most prominent features are congenital binocular cataract, central nerve growth retardation and low molecular weight proteinuria (LMWP). There are 10 types of inositol-5 phosphatase in the human body, and the phosphatidylinositol-5 phosphatase (OCRL 1), which is encoded by the OCRL gene. OCRL 1 is widely present in cells by hydrolyzing phosphatidylinositol 4,5-diphosphate (PIP2) and interacting with small GTPases to regulate actin polymerization, intracellular signaling, vesicle transport, cilia formation, and other physiological processes^[1]. Mutations in the OCRL gene can lead to two diseases: Dent-2 syndrome and Lowe syndrome. There are a total of 24 exons on the OCRL gene, and literature has shown that truncation mutations in exons 1–7 of OCRL lead to Dent-2, while truncation mutations in exons 8–24 lead to Lowe syndrome^[2]. The most important cause of premature death caused by Lowe syndrome is the gradual decline in renal function, ultimately leading to end-stage renal disease (ESRD)^[3].

The patient (III-1) was diagnosed with long-term proteinuria, and physical examination showed that the patient had delayed growth. Further examination revealed a history of congenital cataracts. Through whole exome sequencing, it was found that the patient had a missense mutation on exon 21 (c.2302A > T, p.Ile768Phe), which is a newly discovered mutation and suggests ocular brain renal syndrome. The patient's cousin (III-4) has similar clinical manifestations, including congenital bilateral cataracts, mild developmental abnormalities, and low molecular weight proteinuria. Through genetic verification of four children in a family, it was found that the patient's cousin also a Lowe syndrome patient, and the mothers of both patients (II-2, II-3) X-linked invisible carriers. The maternal grandparents (I-1, I-2) of the patient are healthy and have no relevant clinical manifestations, but unfortunately, genetic validation has not been conducted on the maternal grandparents of the patient. In the early detection of Lowe syndrome, genetic validation of other children in the family can detect the disease earlier, guide treatment, and delay disease progression.

1. Case report (I)

1.1 Clinical Information

Male,12 years ols, was admitted to the hospital because of "the foam in urine increased after birth, and the positive urinary protein was found for 2 days". The patient is G1P1, who was delivered after a full-term cesarean section and had a birth weight of 3600g. Discovered bilateral cataracts 2 months after birth, and the patient underwent cataract surgery. Usually, the child's attention is not focused, their academic performance is poor, and intelligence tests indicate a level below 99%.

Physical examination: Height 142.1cm (below growth curve P3). Slightly slow in response, able to engage in basic normal conversation, with inward strabismus in both eyes, horizontal tremors in the eyeballs, large and round pupils, and good light reflection. There are no abnormalities in the heart, lungs, and abdomen. Muscle strength of limbs is grade V, muscle tone is normal, and tendon reflexes are not elicited. Standing on one foot, unstable jumping on both feet, abnormal gait posture during walking, positive results in finger nose test and heel knee tibia test. The meningeal irritation sign and pathological sign were not introduced.

1.2 Auxiliary inspection

Elevated intraocular pressure in both eyes(31mmHg).

Head MRI shows patchy long T2 and FLAIR high signal shadows around the lateral ventricle of the parietal occipital temporal lobe and left accessory sinusitis (Fig. 1).

Urinary routine: Protein 2+, RBC13.7/HPF. 24-hoururine white 0.99g.24-hour urine calcium 5.94 mmol. Urinary and renal premature loss: urine microalbumin (256mg/L), urine transferrin (18mg/L), urinary ɑ-1-microglobulin (262 mg/L), N-acetyl β-D-glucosaminidase (17IU/L), proteinuria mainly characterized by renal tubular injury.

(Fig. 1 Patchy long T2 and FLAIR high signal shadows around the lateral ventricle of the parietal occipital temporal lobe, left accessory sinusitis)

1.3 Whole Exome Gene Sequencing

The child has congenital bilateral cataracts, comprehensive developmental disorders, and tubular proteinuria, was suspected of having hereditary kidney disease. With the consent of the patient and their parents, whole exome sequencing of the patient's genomic DNA was performed, and genetic validation was performed on their parents. The sequencing was completed by Beijing Maikino Medical Laboratory. Suspected pathogenic genes were detected that could explain the phenotype of the patient, originating from a missense mutation in the mother's OCRL gene at base 2302 (A > T), causing the encoded protein to change from isoleucine to phenylalanine at position 768 (Fig. 2). This pathogenic mutation has not been reported and is a novel mutation. Subsequently, homologous gene validation was performed on the younger brother, sister, and cousin (III-2, III-3, III-4) of the patient, and it was found that patient’s cousin had homologous gene mutations.

(Fig. 2: Whole exome gene sequencing: NM_000276.4, exon21, c.2302A > T (p. lle768phen) The mutation is located on the X chromosome and originates from the mother of the affected child.)

1.4 Follow up

The patient was initially diagnosed with "LS" and then orally treated with "Hydrochlorothiazide, Potassium Citrate Granules". Regular reexamination showed that urinary protein quantification fluctuated between 0.97–1.46 g/24 h, HGB fluctuated between 98–120 g/L, blood potassium fluctuated between 2.69–4.34 mmo1/L, SCr fluctuated between 42–91 µmo1/L, and BUN fluctuated between 4.94–17.67 mmo1/L. One year later, the patient's condition fluctuated: SCr 331 mo/L, BUN 28.95 mmol/L, CCr 21.5 ml/min, and had into “stage IV chronic kidney disease”.

2. Case Report (II)

2.1 Clinical Information

Male, 3 years old, was admitted to the hospital because of "the increase of foam in urine for one year and the positive urinary protein for five days". One year ago, no obvious inducement was found to increase the foamn in urine, and there was no decrease or edema in urine volume. 5 days ago, the urine routine test results were obtained: urine protein+, the cousin of the first patient.

Patient is G2P2, born at term with a birth weight of 3200g. After birth, congenital bilateral cataracts were discovered, and at the age of one year, bilateral lens extraction surgery was performed. The child's development is delayed: turn over at 6–7 months, sit alone and cannot crawl at 1 years old, walk alone at 2 years old, call "dad or mom" around 2 years old, and can currently express and communicate normally without hearing abnormalities.

Physical examination: Height 96.5cm (located on the growth curve P3-P10). Both have large horizontal tremors, strabismus, no restricted eye movement, and both pupils are large and round (2.5 mm to the left and 2.5 mm to the right), with good light reflection. No obvious abnormalities were found in the physical examination of the heart, lungs, and abdomen. Muscle strength of limbs is grade V, with normal muscle tone.

2.2 Auxiliary inspection

Gese II developmental diagnostic scale: 9 months behind their peers.

Head MRI: Multiple patchy can be seen the white matter of the bilateral frontal and parietal lobes and around the lateral ventricles, with slightly longer T1 and slightly longer T2 high FLAIR signals and widened bilateral ventricles (Fig. 3).

Urinary routine: protein 2+, occult blood 1+. 24-hour urine protein 430 mg/24h. 24-hour urine calcium 6.24 mmol/L. Urinary and renal premature loss: urinary microalbumin 262 mg/L, urinary transferrin 267 mg/L, urinary alpha-1-microglobulin 332 mg/L, N-acetyl β-D-glucosaminidase 23.36 IU/L, proteinuria mainly caused by renal tubular injury.

(Fig. 3 Head MRI shows multiple patchy shadows in the white matter of the bilateral frontal and parietal lobes and around the lateral ventricles, with slightly longer T1 and slightly longer T2 high FLAIR signals and widened bilateral ventricles).

2.3 Whole Exome Gene Sequencing

The cousin of the patient is Lowe syndrome. Based on the clinical manifestations, imaging, and laboratory examination results of the patient, it is suspected that the patient has hereditary kidney disease. With the consent of the parents, whole exome sequencing was performed on the genomic DNA of the patient and their parents. The same variation originated from the mother (II-3), with the OCRL gene c.2302A > T (p.lle768phen) (Fig. 4).

(Fig. 4 Whole exon gene sequencing: NM_000276.4; exon21; c.2302A > T (p. lle768phen) The mutation is located on the X chromosome and originates from the mother of the affected child.)

The OCRL gene is located on Xq25-Xq26, and the encoded OCRL 1 protein is located in many subcellular locations, including the Golgi apparatus, lysosomes, and plasma membrane. It participates in intracellular signal transduction and regulates vesicle transport by hydrolyzing PIP2 and interacting with small GTPases. It also plays a role in the formation of primary cilia in retinal pigment epithelial cells and renal tubular cells^[4].

OCRL gene mutations can cause Dent-2 and Lowe syndrome, both of which are rare X-linked recessive inherited diseases and are more common in male patients. Dent-2 is characterized by proximal tubular dysfunction and high urinary calcium, with few extrarenal manifestations ^[5]. Lowe's syndrome is a more severe hereditary, characterized not only by progressive renal failure characterized by low molecular weight proteinuria, high urinary calcium, and tubular injury, but also by congenital cataracts in both eyes and neurological and psychiatric involvement. Children with Lowe's syndrome often have congenital cataracts at birth and can undergo early lens extraction. The earliest diagnosis was found during pregnancy when ultrasound examination revealed the presence of bilateral cataracts in the fetus. At 26W of pregnancy, genetic identification was performed through amniocentesis to diagnose Lowe's syndrome ^[6]. As children grow up, they may also exhibit other eye symptoms, such as glaucoma, corneal scars, visual impairments, etc. The neurological and psychiatric symptoms of Lowe syndrome often manifest as intellectual disabilities, behavioral abnormalities, irritability, aggression, and stereotyped movements. About 50% of children have seizures, and the incidence of self-harm is high; Head MRI shows high-intensity lesions in the ventricles, periventricular and deep white matter on T2 signal, which often appear in the later stages of the disease and have relatively stable morphology and location without significant clinical significance^[7]. Children with Lowe syndrome often have low molecular weight proteinuria and varying degrees of renal performance^[8]. In severe cases, there is a progressive decline in renal function, often leading to end-stage renal disease in the 20th or 30th year. Other renal manifestations include high urinary calcium, amino acid urine, and metabolic acidosis. At present, there is no specific medication for treatment, mainly symptomatic treatment, to delay the decline of renal function. Children with Lowe syndrome often do not have a lifespan exceeding 40 years old.

The mRNA transcribed by the OCRL gene contains 24 exons, and mutations that cause Dent-2 edisease often occur in the first 7 exons^[1]. About half of moutation types that cause Lowe syndrome are missense and nonsense mutations, mainly occurring in exons 8 to 24 containing the 5-phosphatase domain and ASH RhoGAP domain^{[2, 9]}. Pathological studies have shown that mutations in the 5-phosphatase domain can lead to functional defects in OCRL1, affecting vesicular transport and endocytosis; Mutations in the ASH RhoGAP domain can affect cell activation of the mTOR signaling pathway, leading to lysosomal transport dysfunction^[10]. Professor Swetha Ramadesikan has also shown that mutations located in the 5-phosphatase domain can induce Golgi apparatus disruption. In fact, Golgi apparatus disruption can be observed in neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS)^[11], which may be related to neurological and psychiatric symptoms caused by Lowe syndrome. Mutations located in the ASH RhoGAP domain can lead to excessive activation of the mTOR pathway, which in turn affects the assembly of primary cilia^{[12, 13]}. There are a large number of cilia on the proximal renal tubular cells, and there is a certain correlation between cilia motility disorders and renal tubular injury^[14].

A large number of literature mentions a certain correlation between the clinical manifestations of Lowe syndrome and the mutation sites and types of pathogenic genes^{[15, 16, 17]}. Cell experiments have confirmed the heterogeneity of missense mutations in the OCRL gene, some of which may be benign mutations, while others are pathogenic mutations, which are related to the location of missense mutations^[18]. Currently, Clinvar includes 12 types of pathogenic/possible pathogenic missense mutations in Lowe syndrome caused by OCRL gene mutations: p Arg318His, p Cys498Arg, p Arg500Gln, p Asp523Asn, p His524Gln, p Lys525Gln, p Pro526Ser, p Pro526Leu, p Val636Glu, p His660Pro, p Ala797Pro, p Ala861Thr. The two cases reported in this article both have mutations in the OCRL gene (c.2302A > T, p.lle768phen). The literature database and ClinVar database do not include information related to this mutation site, which is a newly discovered mutation site.

The OCRL gene (c.2302A > T, p.lle768phen) is located in the ASH RhoGAP domain, and its main pathogenic mechanism as above: overactivation of mTOR signaling affects ciliary movement. The pathogenic mechanism of this site is consistent with the clinical phenotype of the patient. Both patients presented with proteinuria, progressive renal dysfunction, mild neurological and psychiatric symptoms, only mild developmental abnormalities, and no symptoms such as epilepsy, stereotyped movements, and irritability. The discovery of this site enriched the genotype of Lowe syndrome and further explored the correlation between clinical phenotype and mutation sites.

This report identifies new gene mutation sites in Lowe syndrome and explores the relationship between OCRL gene mutation sites and clinical phenotype based on existing perspectives. After discovering children with Lowe syndrome in clinical practice, conducting gene validation at the same locus in other children in the family can help with early detection, diagnosis, and treatment of the disease.

Ethical approval and consent to participate: Both patients are underage children, and their parents have signed a written informed consent form and agreed to publish the report. This study meets the requirements of the ethics committee.

Availability of data and materials: The data in this study are all from real data during the diagnosis and treatment process, and were obtained according to the requirements of the corresponding authors.

Authors' contributions: HYC and WXL wrote a manuscript analyzing and explaining the relationship between Lowe genotype and phenotype. WL conducted a genotype search for Lowe syndrome and determined that the mutation type in the patient was a significant new mutation. SXY participates in clinical data summary and image editing. HPT and WY guide patient management. All authors participated in the revision of the manuscript. All authors have read and approved the final manuscript.

Acknowledgements: Thanks for the support and cooperation of the children and their families.

Funding: There is no financial support for this job.

Conflict of Interest Statement: This article is completed in the study and work, there is no conflict of interest.

Mehta ZB, Pietka G, Lowe M. The cellular and physiological functions of the Lowe syndrome protein OCRL1. Traffic[J]. 2014;15(5):471–87.
Sakakibara N, Ijuin T, Horinouchi T, et al. Identification of novel OCRL isoforms associated with phenotypic differences between Dent disease-2 and Lowe syndrome. NEPHROL DIAL TRANSPL[J]; 2022. p. 37.
Preston R, Naylor RW, Stewart G et al. A role for OCRL in glomerular function and disease. PEDIATR NEPHROL[J]. 2020; 35.
Ke YH, He JW, Fu WZ et al. Identification of two novel mutations in the OCRL1 gene in two Chinese families with Lowe syndrome. NEPHROLOGY[J]. 2012; 17.
Sakakibara N, Nagano C, Ishiko S et al. Comparison of clinical and genetic characteristics between Dent disease 1 and Dent disease 2. PEDIATR NEPHROL[J]. 2020; 35.
Rouxel F, Fauré J, Faure JM et al. Prenatal diagnosis of Lowe syndrome in a male fetus with isolated bilateral cataract. Heliyon[J]. 2022; 8.
Bökenkamp A, Ludwig M. The oculocerebrorenal syndrome of Lowe: an update. PEDIATR NEPHROL[J]. 2016; 31.
Bockenhauer D, Bokenkamp A, van't Hoff W et al. Renal phenotype in Lowe Syndrome: a selective proximal tubular dysfunction. CLIN J AM SOC NEPHRO[J]. 2008; 3.
Suarez-Artiles L, Perdomo-Ramirez A, Ramos-Trujillo E, Claverie-Martin F. Splicing Analysis of Exonic OCRL Mutations Causing Lowe Syndrome or Dent-2 Disease. Genes (Basel)[J]. 2018;9(1):15.
Karabiyik C, Son SM, Rubinsztein DC. Lysosome positioning and mTOR activity in Lowe syndrome. EMBO REP[j]. 2021-07-05;22(7):e53232.
Martínez-Menárguez JÁ, Tomás M, Martínez-Martínez N et al. Golgi Fragmentation in Neurodegenerative Diseases: Is There a Common Cause? Cells. 2019; 8 Cells.
Madhivanan K, Ramadesikan S, Hsieh WC et al. Lowe syndrome patient cells display mTOR- and RhoGTPase-dependent phenotypes alleviated by rapamycin and statins.HUM MOL GENET[J]. 2020; 29.
Ramadesikan S, Skiba L, Lee J et al. Genotype & phenotype in Lowe Syndrome: specific OCRL1 patient mutations differentially impact cellular phenotypes. HUM MOL GENET[J]. 2021; 30.
Eymael J, Willemsen B, Xu J et al. Motile Cilia on Kidney Proximal Tubular Epithelial Cells Are Associated With Tubular Injury and Interstitial Fibrosis. Front Cell Dev Biol[J]. 2022; 10.
Zaniew M, Bökenkamp A, Kolbuc M et al. Long-term renal outcome in children with OCRL mutations: retrospective analysis of a large international cohort. NEPHROL DIAL TRANSPL[J]. 2018; 33.
Zhang L, Wang S, Mao R et al. Genotype-Phenotype Correlation Reanalysis in 83 Chinese Cases with OCRL Mutations. GENET RES[J]. 2022-01-01;2022:1473260.
Recker F, Zaniew M, Böckenhauer D et al. Characterization of 28 novel patients expands the mutational and phenotypic spectrum of Lowe syndrome. PEDIATR NEPHROL[J]. 2015; 30.
Lee JJ, Ramadesikan S, Black AF et al. Heterogeneity in Lowe Syndrome: Mutations Affecting the Phosphatase Domain of OCRL1 Differ in Impact on Enzymatic Activity and Severity of Cellular Phenotypes. Biomolecules[J].2023;13.

No competing interests reported.

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Two cases of Lowe syndrome caused by a novel mutation in OCRL gene in a family

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Abstract

Figures

Background

Case presentation

1. Case report (I)

2. Case Report (II)

Discussion

Declarations

References

Additional Declarations

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