Endocrine and behavioural features of Lowe syndrome and their potential molecular mechanisms

Abstract

Background: Lowe syndrome (LS) is an X linked disease caused by pathogenic variants in the OCRL gene that impacts approximately 1 in 500 000 children. Classic features include congenital cataract, cognitive/behavioural impairment and renal tubulopathy.

Methods: This study is a retrospective review of clinical features reported by family based survey conducted by Lowe Syndrome Association. Frequency of non-ocular clinical feature(s) of LS and their age of onset was summarised. An LS-specific therapy effectiveness scale was used to assess the response to the administered treatment. Expression of OCRL and relevant neuropeptides was measured in postmortem human brain by qPCR. Gene expression in the mouse brain was determined by reanalysis of publicly available bulk and single cell RNA sequencing.

Results: A total of 137 individuals (1 female, 89.1% white, median age 14 years (range 0.8-56)) were included in the study. Short stature (height <3rd percentile) was noted in 81% (n=111) individuals, and 15% (n=20) received growth hormone therapy. Undescended testis was reported in 47% (n=64), and median age of onset of puberty was 15 years. Additional features were dental problems (n=77, 56%), bone fractures (n=63, 46%), hypophosphataemia (n=60, 44%), developmental delay and behavioural issues. OCRL is expressed in human and mouse hypothalami, and in hypothalamic cell clusters expressing Ghrh, Sst, Oxt, Pomc and pituitary cells expressing Gh and Prl.

Conclusions: There is a wide spectrum of the clinical phenotype of LS. Some of the features may be partly driven by the loss of function of OCRL in the hypothalamus and the pituitary.

Keywords: endocrinology; genetics, medical.

Figure 1.

Graphical abstract

Figure 2.

Clinical features of LS with the reported age. The horizontal box plots show age of onset, median, interquartile range and outliers. The numbers indicate the aggregate subjects with the reported feature.

Figure 3.

Anthropometric features of LS a) Height for age. Each data point indicates a subject. Blue line is the 3^rd and green 50^th percentile. The dashed line is the fitted line for height for subjects with LS. b) BMI calculated from reported height and weight for age. Each data point represents a subject. The black line indicates 5^th, blue 85^th, orange 95^th and red 120% of 95^th percentile for age. All references based on CDC 2000 growth charts.

Figure 4.

a) Relative expression of neuropeptides and OCRL in postmortem human hypothalamus, cortex and fibroblasts, b) Bulk RNA seq data expression from different parts of mouse brain -neuropeptides and Ocrl and its paralog, Inpp5b and neuropeptides. c) Expression of Ocrl in neuronal cell clusters from mouse arcuate nucleus of the hypothalamus. Of the 21,086 analyzed cells, 13,079 were identified as neurons and 8,007 as non-neurons based on the expression of the canonical neuronal marker Tubb3. Colored bars indicate log-transformed and scaled expression of Ocrl. Cluster identities based on the highest gene expression: n1.Hdc (n=50), n2. Gm8773/Tac1 (n=83), n3. Th/Sst (n=30), n6. Oxt (n=36), n10. Ghrh (n=504), n14.Pomc/Ttr (n=512), n.15 (Pomc/Anxa2, n = 369), n19. Gpr50 (n=67), n21.Pomc/Glipr1 (n=310), n26. Htr3b (n=486), n29. Grfp (n=745), and n31. Slc17a6/Fam19a2 (n=171). d) Expression of Ocrl in mouse pituitary cell clusters expressing Gh (Cluster 4, expressing Pappa2, n= 1,181), pituitary progenitors (Cluster 9, expressing Sox2, n=480), intermediate lobe melanotropes (Cluster 14, expressing Pax7, n=305) and lactotrophs (Cluster 15, expressing Prl, n=256). Abbreviations: GHRH–growth hormone releasing hormone, POMC – pro-opiomelanocortin, GNRH = gonadotrophin releasing hormone, TRH = thyrotropin releasing hormone, OXT – oxytocin, SST – somtatostatin, PVH–paraventricular nucleus, LH–lateral hypothalamus, ARC–arcuate hypothalamus, eHYP–embryonic hypothalamus