Plasma and Urinary Sulfate Determination in a Cohort with Autism

Abstract

Sulfate is important for mammalian development but is not routinely measured in clinical settings. The renal NaS1 sulfate transporter maintains circulating sulfate levels and is linked to renal sulfate wasting in mice. Some autistic individuals exhibit renal sulfate wasting, but the etiology is yet unknown. We measured plasma and urinary sulfate levels, calculated the fractional excretion index (FEI) of sulfate, and screened for two loss-of-function NaS1 sequence variants (R12X and N174S) in 23 autistic individuals. The FEI sulfate values ranged from 0.13 to 0.50. NaS1 variants were detected in 18 of the 23 individuals (11 heterozygous N174S, four homozygous N174S, two heterozygous R12X, and one individual carried both R12X and N174S). Those individuals with neither sequence variant had FEI sulfate ≤ 0.34, whereas FEI sulfate ≥ 0.35 was found in about 60 % (11 of 18) of individuals that had R12X and/or N174S. This study links renal sulfate wasting with loss-of-function NaS1 sequence variants in humans.

Genetics and pathophysiology of mammalian sulfate biology

“…Disruption of the SLC13A1 gene leads to renal sulfate wasting and hyposulfataemia in humans, mice, dogs and sheep (Dawson et al, 2003;Bowling et al, 2012;Neff et al, 2012;Zhao et al, 2012), whereas loss of the SLC13A4 gene blocks placental sulfate supply to the developing fetus, which causes severe developmental abnormalities and late gestational fetal death in mice (Rakoczy et al, 2015b). Interestingly, disruptions to the SLC13A1 and SLC13A4 genes do not cause any major cellular pathology in the tissues where these genes are expressed but rather lead to reduced circulating sulfate levels which in turn decreases sulfonation capacity in cells throughout the body (Dawson et al, 2003;Lee et al, 2006;Rakoczy et al, 2015b).…”

“…The landmark paper reporting sulfate activation to PAPS (Lipmann, 1958) and the following identification of sulfotransferases (Lipmann, 1958;Gamage et al, 2006), as well as the characterisation of animal models of perturbed sulfate homeostasis (Tables 5-7), have led to our current understanding of sulfate biology genetics, and the physiological importance of sulfate in modulating the biological activity of neurotransmitters (Coughtrie et al, 1998;Lee et al, 2007), steroids (Dawson, 2012), thyroid hormone (Richard et al, 2001;Wu et al, 2005), proteoglycans and xenobiotics (Habuchi et al, 2004;Klüppel, 2010). …”

“…Whilst there are numerous pathological features associated with the 43 genes, the following sections focus on predominant features, including neurological dysfunction, skeletal dysplasias, reduced fecundity and reproduction, and cardiovascular pathologies. The potential involvement of several sulfate maintenance genes in cancer has also gained attention from the scientific community in recent years, and those findings have been reviewed elsewhere (Dawson et al, 2010a;Dawson, 2012;Daniels and Kadlubar, 2013;Rižner, 2016).…”

“…1A) (Dawson, 2011). In most cases, sulfonation leads to the inactivation of steroids, thyroid hormone and neurotransmitters, as well as Phase II metabolism and detoxification of xenobiotics and certain drugs such as paracetamol (Mulder and Jakoby, 1990;Darras et al, 1999;Richard et al, 2001;Yamaguchi, 2001;Stanley et al, 2005;Alnouti, 2009;Dawson, 2012). Sulfonation of glycosaminoglycans is also required to maintain the structure and function of tissues (Habuchi et al, 2004;Klüppel, 2010).…”

The Biological Roles of Steroid Sulfonation

“…Mice lacking the NaS1 or SAT1 genes have sulfate wasting into the urine which leads to low blood sulfate levels (hyposulfataemia) [12,13]. Humans with loss of function mutations (R12X and N174S) in the NaS1 gene also exhibit renal sulfate wasting and hyposulfataemia [14]. This depletion of sulfate from circulation reduces sulfate availability to cells throughout the body and leads to a reduced intracellular sulfate conjugation (sulfonation) capacity, as shown in the NaS1 and SAT1 null mice [12,13,15].…”