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This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. 
 

CYSTINURIA: GENETIC 

ASPECTS AND NOVEL 

PHARMACOTHERAPEUTICS 
 

DIANA STACHULA, 

AMRIK SAHOTA (FACULTY ADVISOR) 

 

✵  ABSTRACT 
This review provides an overview of the ge-

netic aspects of cystinuria, as well as the novel phar-

macotherapeutics that could potentially be used to 

treat the disease. Cystinuria is an inherited disorder 

characterized by the formation of painful stones in 

the kidneys, bladder, and other parts of the renal 

system. Currently, mutations responsible for cysti-

nuria have been identified in two genes (SLC3A1 

and SLC7A9 ), and cystinuria patients are catego-

rized based on their genotypes - which versions, or 

alleles, of these genes they have (mutated or wild-

type). Regardless of genotype, however, current 

treatments for all cystinuria patients have significant 

limitations. This has led researchers to search for 

more promising therapeutics. One potential treat-

ment uses cystine analogs—compounds that are 

structurally similar to cystine, which is the naturally 

occurring chemical substance from which the 

stones are formed. These compounds have demon-

strated the ability to inhibit stone formation by stunt-

ing cystine crystallization – the process by which cys-

tine crystals aggregate to form stones. Gene ther-

apy may also be used to treat cystinuria in the future 

by replacing mutated copies of SLC3A1 and 

SLC7A9 with healthy ones. Technological advance-

ments and an improvement of our understanding of 

how gene therapy functions in the renal system 

could reveal even more treatment possibilities. 

 

1  INTRODUCTION 
Cystinuria generally arises from mutations 

in the SLC3A1 and SLC7A9 genes. There are likely 

more genetic factors that contribute to the disease 

that are yet to be identified, as 5% of cystinuria pa-

tients do not have mutations in either of the two 

genes. (Sahota et al., 2019). SLC3A1 and SLC7A9 

encode crucial components of the biochemical 

pathway responsible for the reabsorption of dibasic 

amino acids in the renal system. Dibasic amino acids 

are organic compounds that form proteins and con-

tain two basic functional groups, typically amino 

groups (NH2). One dibasic amino acid is cystine (FIG-

URE 2), which is made of two cysteine molecules 

joined by a disulfide bond (S - S) (FIGURE 1). The de-

fective reabsorption of cystine from the kidneys into 

the bloodstream causes its supersaturation in urine 

and the formation of cystine stones in the kidneys, 

bladder, and ureters (Sahota et al., 2019). Cystine 

stones are jagged in shape and are considered to 

be the hardest stones formed in the human renal 

system (Ringdén & Tiselius, 2007). Most cystinuria 

patients that develop their first stone in adolescence 

are prone to recurrent stone formation throughout 

their lifetimes (Rogers et al., 2007). In addition to ab-

dominal pain, patients may also experience nausea, 

hematuria (blood in urine), recurrent urinary tract in-

fections, and kidney failure (Mattoo & Goldfarb, 

2008). Increased fluid intake, reduced protein con-

sumption, and the use of currently available medi-

cations have proven to be less-than-ideal treatment 

methods for the disease (Sahota et al., 2019). Poten-

tial novel treatments of cystinuria have been studied 

using Slc3a1 and Slc7a9 knockout mouse models, 

which are mice with mutated, nonfunctional ver-

sions of the SLC3A1 and SLC7A9 genes (Sahota et 

al., 2019). Cystine diesters, such as cystine di-

methylester (CDME) (FIGURE 3), and cystine diamides,  

FIGURE 1: Cysteine is an amino acid with a thiol side chain 

(R-SH). Two cysteine molecules can be oxidized to form 

cystine (FIGURE 2). 



ARESTY RUTGERS UNDERGRADUATE RESEARCH JOURNAL, VOLUME I, ISSUE IV 

 

FIGURE 2: Cystinuria patients form stones made of cystine, 

an organic molecule containing a disulfide bridge (S – S) 

and two amine groups (-NH2). 

 

 
FIGURE 3: CDME is an example of a cystine diester, a type 

of cystine analog. Like cystine, it contains a disulfide 

bridge (S – S) and two amine groups (-NH2). 

 

 
FIGURE 4: L-cystine bis(N′-methylpiperazide) is an example 

of a cystine diamide, a type of cystine analog. Like cys-

tine, it contains a disulfide bridge (S – S) and two amine 

groups (-NH2). 
 

such as L-cystine bismorpholide and L-cystine 

bis(N′-methylpiperazide) (FIGURE 4), all of which are 

analogs of cystine (FIGURE 2), have demonstrated 

their effectiveness as potential treatments for cysti-

nuria through their abilities to inhibit cystine crystal 

growth in these mouse models (Yang et al., 2018). 

Continued study of cystine stone formation inhibi-

tors, as well as gene therapy, will likely generate 

promising new treatments for human cystinuria pa-

tients.  

 

2 CYSTINURIA: ETIOLOGY AND  

EPIDEMIOLOGY 
TRANSPORT DEFECT 

Genetic mutations in SLC3A1 and SLC7A9 

cause the defective reabsorption of several dibasic 

amino acids — cystine, ornithine, lysine, and arginine 

(COLA) — from the kidneys into the bloodstream 

(FIGURE 5) (Sahota et al., 2019). More specifically, 

these mutations disrupt the COLA transporter 

(b0,+), which is a heterodimer, or a molecule made 

up of two protein components (Sahota et al., 2019). 

SLC3A1 and SLC7A9 each encode one of these 

components (Sumorok & Goldfarb, 2013); SLC3A1 

encodes the rBAT subunit, while SLC7A9 encodes 

the b0,+ AT subunit (FIGURE 6) (Sahota et al., 2019). 

Mutations in either gene will cause a defect in the 

corresponding subunit, leading to the defective re-

absorption of the COLA amino acids (Sumorok & 

Goldfarb, 2013). Since cystine is the least soluble of 

the COLA amino acids, it has a greater ability to crys-

tallize in the urinary tract and form stones when im-

properly reabsorbed (Sahota et al., 2019). 

 

STONE FORMATION 

Cystine stones are thought to form by free 

solution crystallization, the process by which super-

saturated solutions transform into solids (Coe et al., 

2010). When cystine is supersaturated in urine, it 

crystallizes into stones that can be found freely 

throughout the renal system (Coe et al., 2010), 

though they are predominantly found in the termi-

nal collecting ducts within the kidneys (Khan et al., 

2016). These stones are named depending on their 

specific location (FIGURE 7). Their mobility within the 

renal system allows them to be easily removed dur-

ing surgery; crystals of large size wash away when 

surgically exposed (Coe et al., 2010). 

 

 



ARESTY RUTGERS UNDERGRADUATE RESEARCH JOURNAL, VOLUME I, ISSUE IV 

 

FIGURE 5: Mutations in the SLC3A1 and SLC7A9 genes cause the defective reabsorption of the COLA amino acids from the 

proximal convoluted tubule into the bloodstream. These dibasic amino acids proceed through the rest of the renal system 

and are excreted in urine. Created with BioRender.com. 

 

 

FIGURE 6: SLC3A1 encodes the rBAT subunit (green) and SLC7A9 encodes the b0,+ AT subunit (blue) of the COLA trans-

porter (b0,+), which is responsible for the reabsorption of the COLA amino acids in the renal system. Cystine is reduced to 

two cysteine molecules when it is reabsorbed into the bloodstream. 

 

 

 

 

EPIDEMIOLOGY

Although cystine stones make up only ap-

proximately 1% of all kidney stones, cystinuria is still  

one of the most commonly inherited genetic disor-

ders (Mattoo & Goldfarb, 2008). The disease has a 

global prevalence of approximately 1:7,000, rang-

ing from 1:2,500 in Libyan Jews to 1:100,000 in 

Swedes. In the United States, approximately 1 in 

15,000 adults have cystinuria (Mattoo & Goldfarb, 

2008). Men are twice as likely as women to develop 

cystine stones (Leslie, Sajjad & Nazzal, 2020). This 

may be due to shorter urethral length or factors that 

inhibit cystine crystal aggregation in females (Sa-

hota et al., 2019). 

Patients typically first present a stone be-

tween the ages of 2 and 40, with a median onset age  

of 12 in males and 15 in females (Rogers et al., 

2007). Approximately two thirds of cystinuria pa-

tients develop stones in both kidneys, while one 



ARESTY RUTGERS UNDERGRADUATE RESEARCH JOURNAL, VOLUME I, ISSUE IV 

 

third only form stones in a single kidney 

(Usawachintachit et al., 2018). Among patients who 

develop stones, over 60% experience recurrent 

stone formation, with males forming new stones 

about every 3 years and females forming new 

stones about every 5 years (Dello Strologo et al., 

2002). In addition to higher recurrence rates, males 

also typically experience more aggressive disease 

symptoms that may require more surgical interven-

tions (Edvardsson et al., 2013). 

 

 
FIGURE 7: Cystine stones are found freely throughout the 

renal system. Created with BioRender.com. 

 

3 GENETICS 
INHERITANCE AND GENOTYPES 

Cystinuria patients are classified depending 

on which of their genes are mutated. Those with 

type A, or type I, cystinuria have a mutation in 

SLC3A1 on chromosome 2. Those with type B, or 

non-type I, cystinuria have a mutation in SLC7A9 on 

chromosome 19 (Fazaeli et al., 2017). Every person 

has two copies of each gene. Mutations in SLC3A1 

are inherited through an autosomal recessive pat-

tern of inheritance (both copies of the gene must be 

mutated for disease presentation) (Martell et al., 

2017). Meanwhile, mutations in SLC7A9 follow an 

autosomal dominant pattern of inheritance with in-

complete penetrance; typically (only one mutated 

copy of the gene needs to be present to allow for 

the formation of cystine stones) (Martell et al., 2017). 

Rarely, patients have type AB cystinuria; people who 

fall under this category have two mutated copies of 

one of the genes as well as one mutated copy of the 

other (Sumorok & Goldfarb, 2013). Depending on 

which gene has two mutated copies and which has 

one mutated copy, patients can be designated as 

either type AAB or type ABB (Sumorok & Goldfarb, 

2013). 

As aforementioned, both copies of SLC3A1 

must be mutated for disease presentation, so 

SLC3A1 heterozygotes, who only have one mutated 

copy, should not present stones or any characteris-

tics of cystinuria. SLC7A9 heterozygotes, however, 

may present cystinuria symptoms such as variable 

urinary levels of COLA (Edvardsson et al., 2013). 

SLC7A9 heterozygotes are unlikely to develop 

stones unless urine volumes are low or protein in-

take is significantly elevated (Sahota et al., 2019). 

 

MUTATIONS 

Over 400 total mutations have been identi-

fied in SLC3A1 and SLC7A9 (Stenson et al., 2003), 

including missense, nonsense, splicing, regulatory, 

deletion, insertion, indel, duplication, and rear-

rangement mutations (Stenson et al., 2003). Each of 

these mutation types alters the DNA sequences of 

SLC3A1 and SLC7A9, resulting in the formation of 

altered or truncated proteins (the subunits of the 

COLA transporter). Missense mutations are the larg-

est group of mutations that result in cystinuria. Such 

mutations change a single amino acid in the protein 

being encoded, which can have a range of effects 

on the protein — protein function may be unim-

pacted, impacted to some degree, or lost com-

pletely (Martell et al., 2017). Currently, the impact of 

missense mutations in SLC3A1 and SLC7A9 on pro-

tein function and disease presentation is unclear. 

(Martell et al., 2017).  

TABLE 1 presents the mutation type and num-

ber of mutations found in SLC3A1. Of the 261 muta-

tions identified, data on 210 mutations has been 

made publicly available by the Human Gene Muta-

tion Database (HGMD) from the Institute of Medical 

Genetics in Cardiff. TABLE 2 presents the mutation 

type and number of mutations found in SLC7A9. Of 

the 170 mutations identified, data on 143 mutations 

has been made publicly available by HGMD (Sten-

son et al., 2003). 

 

 



ARESTY RUTGERS UNDERGRADUATE RESEARCH JOURNAL, VOLUME I, ISSUE IV 

 

TABLE 1: SLC3A1 mutations listed in the HGMD database. 

 

TABLE 2: SLC7A9 mutations listed in the HGMD database. 
 

Mutation type Number of mutations 

Missense/nonsense 128 

Splicing  13 

Regulatory  1 

Small deletions  19 

Small insertions  11 

Small indels (insertions + deletions) 2 

Gross deletions 30 

Gross insertions/duplications  5 

Complex rearrangements  1 

Repeat variations  0 

Public total (HGMD Professional 2021.4 total) 210 (261) 

Mutation type Number of mutations 

Missense/nonsense 75 

Splicing  18 

Regulatory  0 

Small deletions  29 

Small insertions  10 

Small indels (insertions + deletions) 1 

Gross deletions 9 

Gross insertions/duplications  1 

Complex rearrangements  0 

Repeat variations  0 

Public total (HGMD Professional 2021.4 total) 143 (170) 



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4 MOUSE MODELS 
KNOCKOUT MOUSE MODELS 

Several mouse models have been gener-

ated to observe the traits associated with types A, B, 

and AB cystinuria (Sahota et al., 2019). Among these 

is a knockout Slc3a1 mouse model, Slc3a1-/-, in 

which both copies of the SLC3A1 gene were mu-

tated to become nonfunctional, or “knocked out” 

(Sahota et al., 2019). Urine analyses have revealed 

the presence of supersaturated cystine crystals in 

the Slc3a1-/- mice (FIGURE 8). Computed tomography 

(CT) scanning was also used to view the cystine 

stones found in these knockouts (FIGURE 9). A Slc7a9-

/- knockout mouse model with deletion mutations in 

both copies of SLC7A9 was also created (Font-

Llitjós et al., 2007). Both type A Slc3a1-/- and type B 

Slc7a9-/- mice presented higher urinary levels of cys-

tine in comparison to wild-type (non-mutated) mice 

(Beckermann et al., 2020; Font-Llitjós et al., 2007). A 

mouse model of type AB cystinuria (Slc3a1+/−, 

Slc7a9+/−) was generated by crossing type A and 

type B mice (Sahota et al., 2019). These type AB 

mice also had COLA hyperexcretion; however, they 

presented more severe stone formation than type A 

or type B mice (Espino et al., 2015). 

 

 
FIGURE 8: The hexagonal cystine crystals observed in an 

Slc3a1-/- mouse. Image provided by Amrik Sahota, Ph.D. 

 

 

 
FIGURE 9: Cystine stones in an Slc3a1 knockout mouse 

(top), shown to scale (bottom). Figure provided by Amrik 

Sahota, Ph.D. 

 

GENDER DIFFERENCES 

Males with cystinuria experience more ag-

gressive disease symptoms than females, a charac-

teristic reflected by Slc3a1-/- mice (Sahota et al., 

2019). Knockout males and females presented cys-

tine crystals of similar size and distribution; how-

ever, bladder stones only formed in a few female 

mice and with a later onset (>18 months) than their 

male counterparts (Sahota et al., 2019). 

Sex differences were not observed in the 

knockout Slc7a9-/- mice, as both males and females 

formed stones in a 1:1 ratio with an onset age of one 

month (Feliubadaló et al., 2003). 

 

5 CURRENT TREATMENTS AND  

LIMITATIONS 
Individuals with cystinuria will experience 

recurrent cystine stone formation throughout their 

lifetimes, so behavioral management and pharma-

cological therapies are often necessary to increase 

quality of life (Siener et al., 2021). Treatment meth-

ods for cystinuria have remained largely unaltered 

for the past few decades. Currently, most cystinuria 

patients are advised to increase their fluid intake 

and reduce their protein and sodium consumption 

https://orcid.org/0000-0002-3603-673X
https://orcid.org/0000-0002-3603-673X
https://orcid.org/0000-0002-3603-673X


ARESTY RUTGERS UNDERGRADUATE RESEARCH JOURNAL, VOLUME I, ISSUE IV 

 

(Siener et al., 2021). In addition to behavioral modi-

fications, urinary alkalinization (increasing urine pH) 

is considered a primary treatment because cystine 

is more soluble at higher pH values (Pearle et al. 

2014). Afflicted individuals may take potassium cit-

rate to achieve a urine pH of 7.0-7.5 (the normal av-

erage urine pH is 6.0) (Pearle et al. 2014). In more 

severe cases, patients may be prescribed thiol 

drugs, which contain a thiol functional group (-SH) 

that binds to cystine (Pearle et al. 2014). 

The previously mentioned treatment meth-

ods all have limitations. Many cystinuria patients 

have trouble adhering to behavioral modifications, 

especially young children who may find it difficult to 

consume large amounts of water (Sahota et al. 

2019). Excess potassium citrate can lead to the for-

mation of calcium phosphate stones (another type 

of kidney stone), and thiol drugs have several dose-

dependent adverse effects (Pereira, Schoolwerth & 

Pais, 2015). Such side effects include, but are not 

limited to, skin diseases, liver abnormalities, and 

blood disorders (DeBerardinis et al., 2008). There-

fore, there is a clear need for more tolerable, pre-

ventative treatment options. 

Due to the limitations of current treatments, 

most cystinuria patients require multiple surgical in-

terventions throughout their lifetimes. Non-invasive 

stone-removing procedures include extracorporeal 

shockwave lithotripsy (ESWL), which directs a shock 

wave at the stone (Wood et al., 2011). However, cys-

tine stones are somewhat resistant to ESWL, so mul-

tiple rounds of treatment are necessary (Wood et al., 

2011). Furthermore, only 37.5% of cystinuria pa-

tients remain stone-free for three months after un-

dergoing ESWL (Landau et al., 2009). Several con-

current ESWL treatments increase the risk of kidney 

damage. Renal injuries as the result of ESWL in-

clude, but are not limited to, hemorrhages, ruptur-

ing of small veins and capillaries, necrosis (prema-

ture cell death), hematomas (severe bruises), and 

complete loss of kidney function (McAteer & Evan, 

2008).  

 

 

 

 

6 CYSTINE STONE INHIBITORS 
CYSTINE ANALOGS 

Cystine crystallization is a critical step in 

stone formation; therefore, potential treatments for 

cystinuria have been evaluated for their ability to in-

hibit cystine crystallization (Yang et al., 2018). 

Atomic force microscopy (AFM), a high-resolution 

microscopy technique, was used to visualize growth 

on the surface of cystine crystals in the presence of 

31 prospective crystal inhibitors (Poloni et al., 2017). 

The data showed that the most effective inhibitors 

of cystine crystal growth were cystine analogs, also 

known as “molecular imposters.” Cystine diesters 

and cystine diamides, two types of cystine analogs, 

demonstrated the greatest inhibitory effects on cys-

tine crystal growth (Poloni et al., 2017). In the pres-

ence of these inhibitors, cystine crystals were 

smaller and changed shape from hexagonal to te-

tragonal, making them more soluble (Poloni et al., 

2017). Maintaining higher levels of cystine in solu-

tion is crucial to inhibiting cystine crystallization (Hu 

et al., 2016). 

 

CYSTINE DIAMIDES 

A series of cystine diamides were designed, 

synthesized, and then evaluated for their ability to 

inhibit cystine crystallization (Yang et al., 2018). Of 

the synthesized cystine diamides, L-cystine bismor-

pholide and L-cystine bis (N′-methylpiperazide) 

were the greatest crystallization inhibitors; they 

were 7 and 24 times more potent, respectively, as 

well as more stable than a previously studied cystine 

diester, L-cystine dimethylester (CDME) (Yang et al., 

2018). Additionally, L-cystine bis (N′-methylpiper-

azide) has been able to successfully inhibit stone 

formation in an Slc3a1 knockout mouse model, in-

dicating that cystine diamides could potentially be 

used to prevent the formation of cystine stones in 

human cystinuria patients (Yang et al., 2018). How-

ever, because the knockout mice form bladder 

stones rather than kidney stones (Woodard et al., 

2019), the direct application of these results to hu-

man patients may have some limitations.  

Since cystine diamides have greater chemi-

cal stability than cystine diesters (e.g., CDME), they 

are likely more resistant to proteolytic degradation 



ARESTY RUTGERS UNDERGRADUATE RESEARCH JOURNAL, VOLUME I, ISSUE IV 

 

(the breakdown of peptide bonds in an amino acid) 

(Hu et al., 2016). L-cystine bismorpholide and L-cys-

tine bis (N′-methylpiperazide) are more promising 

treatments than CDME not only because of their in-

creased chemical stability, but also because they are 

orally bioavailable (they can be easily ingested by 

mouth and absorbed by the body) (Hu et al., 2016). 

While CDME has been effective in decreasing cys-

tine stone size and mass, its efficacy post oral admin-

istration may be reduced due to esterase-mediated 

hydrolysis, a process causing the degradation of 

diesters (Hu et al., 2016). Furthermore, AFM has re-

vealed that cystine diamides are better than CDME 

and other cystine diesters at maintaining higher lev-

els of cystine in solution, an important factor in pre-

venting cystine crystals from aggregating into 

stones. (Hu et al., 2016). 

 

7 FUTURE DIRECTION 
As our knowledge and understanding of the 

pathophysiology of cystinuria expands, new thera-

pies and treatments will continue to emerge. Ad-

vancements in imaging technology and its interpre-

tation will progress the current treatment manage-

ment systems toward more effective methods. The 

application of AFM in identifying crystal growth in-

hibitors and the continued use of mouse models will 

provide greater insight into these alternative thera-

pies (Pereira et al., 2015).  

Aside from cystine analogs, gene therapy 

appears to be a promising treatment for cystinuria 

as well. Gene therapy is a disease treatment tech-

nique in which a diseased gene copy is replaced 

with a healthy gene copy in a living organism. 

CRISPR/Cas9 precision gene editing was recently 

utilized to create a Slc7a9-/- knockout mouse model 

of cystinuria (Bai et al., 2019). Research groups are 

attempting to use gene therapy to repair the Slc7a9 

deletions in these knockouts. However, multiple ob-

stacles have presented themselves, including im-

mune responses against vectors, which are organ-

isms, usually bacteria, that deliver foreign DNA to 

recipient cells (Bai et al., 2019). The location and 

anatomy of the kidney could be causing difficulties 

in vector delivery (Bai et al., 2019). More must be 

learned about applying gene therapy technologies 

to the renal system to proceed (Bai et al., 2019). If 

research efforts are successful, gene therapy could 

become an ideal, one-time treatment for cystinuria 

as it has been for other rare genetic disorders (e.g., 

spinal muscular atrophy) (Mendell et al., 2017). Even 

though there is great diversity in the mutations that 

can lead to cystinuria (Stenson et al., 2003), gene 

therapy is versatile in the mutations it can correct 

with a healthy gene copy (Luther et al., 2018). 

 

8 CONCLUSIONS 
Cystinuria is a genetic disorder that causes 

the formation of cystine stones in the renal system 

as a result of mutations in the SLC3A1 and SLC7A9 

genes. Distributions of the disease vary by popula-

tion, although males are more likely than females to 

have severe disease presentation. Because cystine 

stones have a high recurrence rate, cystinuria pa-

tients frequently require several surgical interven-

tions throughout their lifetimes. Current treatments, 

such as increased fluid intake, urine alkalinization, 

and thiol drugs, are aimed at delaying, but not nec-

essarily eliminating, the need for surgical interven-

tions. This renders them nonoptimal, especially be-

cause they may cause severe side effects. Cystine 

analogs, particularly cystine diesters (e.g. CDME) 

and cystine diamides (e.g., L-cystine bismorpholide 

and L-cystine bis (N′-methylpiperazide)), have 

demonstrated their ability to effectively inhibit cys-

tine crystal growth and, in some cases, stone for-

mation. This qualifies them as potential alternatives 

to the cystinuria treatments currently in use. Gene 

therapy has also been considered as a potential 

treatment; however, not enough information about 

its use in the renal system is presently known. With 

continued research, a new treatment that will im-

prove the quality of life of human cystinuria patients 

could be made available in the near future∎ 

 

9 ACKNOWLEDGEMENTS 
Amrik Sahota, Ph.D. (Human Genetics Insti-

tute of New Jersey) provided the images used in 

Figures 6 and 7 of this literature review. I’d like to 

thank him for his contribution and his guidance as a 

research mentor. 



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10  REFERENCES 
[1]  Bai, Y., Tang, Y., Han, P. et al. Gene therapy for cysti-

nuria. Urolithiasis 47, 309–310 (2019).  
HTTPS://DOI.ORG/10.1007/S00240-019-01111-7 

[2] Beckermann, T. M., Welch, R. C., Williams, F. M., Mort-

lock, D. P., Sha, F., Ikizler, T. A., Woodard, L. E., & Wil-

son, M. H. (2020). CRISPR/Cas9 engineering of albino 

cystinuria Type A mice. Genesis (New York, N.Y.: 

2000), 58(5), e23357.  
HTTPS://DOI.ORG/10.1002/DVG.23357 

[3] Coe, F. L., Evan, A. P., Worcester, E. M., & Lingeman, 

J. E. (2010). Three pathways for human kidney stone 

formation. Urological research, 38(3), 147–160.  
HTTPS://DOI.ORG/10.1007/S00240-010-0271-8 

[4] DeBerardinis, R. J., Coughlin, C. R., 2nd, & Kaplan, P. 

(2008). Penicillamine therapy for pediatric cystinuria: 

experience from a cohort of American children. The 

Journal of urology, 180(6), 2620–2623.  
HTTPS://DOI.ORG/10.1016/J.JURO.2008.08.057 

[5] Dello Strologo, L., Pras, E., Pontesilli, C., Beccia, E., 

Ricci-Barbini, V., de Sanctis, L., Ponzone, A., Gallucci, 

M., Bisceglia, L., Zelante, L., Jimenez-Vidal, M., Font, 

M., Zorzano, A., Rousaud, F., Nunes, V., Gasparini, P., 

Palacín, M., & Rizzoni, G. (2002). Comparison be-

tween SLC3A1 and SLC7A9 cystinuria patients and 

carriers: a need for a new classification. Journal of the 

American Society of Nephrology: JASN, 13(10), 2547–

2553.  
HTTPS://DOI.ORG/10.1097/01.ASN.0000029586.17680.E5 

[6] Edvardsson, V. O., Goldfarb, D. S., Lieske, J. C., 

Beara-Lasic, L., Anglani, F., Milliner, D. S., & Palsson, 

R. (2013). Hereditary causes of kidney stones and 

chronic kidney disease. Pediatric nephrology (Berlin, 

Germany), 28(10), 1923–1942.  
HTTPS://DOI.ORG/10.1007/S00467-012-2329-Z 

[7]  Espino, M., Font-Llitjós, M., Vilches, C., Salido, E., Prat, 

E., López de Heredia, M., Palacín, M., & Nunes, V. 

(2015). Digenic Inheritance in Cystinuria Mouse 

Model. PloS one, 10(9), e0137277.  
HTTPS://DOI.ORG/10.1371/JOURNAL.PONE.0137277 

[8] Fazaeli, S., Ashouri, S., Kheirollahi, M., Mohammadi, 

M., & Fazilati, M. (2017). A Novel Mutation in SLC7A9 

Gene in Cystinuria. Iranian journal of kidney dis-

eases, 11(2), 138–141.  

[9]  Feliubadaló, L., Arbonés, M. L., Mañas, S., Chillarón, 

J., Visa, J., Rodés, M., Rousaud, F., Zorzano, A., Pala-

cín, M., & Nunes, V. (2003). Slc7a9-deficient mice de-

velop cystinuria non-I and cystine urolithiasis. Human 

molecular genetics, 12(17), 2097–2108.  
HTTPS://DOI.ORG/10.1093/HMG/DDG228 

[10] Font-Llitjós, M., Feliubadaló, L., Espino, M., Clèries, 

R., Mañas, S., Frey, I. M., Puertas, S., Colell, G., Pal-

omo, S., Aranda, J., Visa, J., Palacín, M., & Nunes, V. 

(2007). Slc7a9 knockout mouse is a good cystinuria 

model for antilithiasic pharmacological stud-

ies. American journal of physiology. Renal physiol-

ogy, 293(3), F732–F740.    
HTTPS://DOI.ORG/10.1152/AJPRENAL.00121.2007 

[11] Hu, L., Yang, Y., Aloysius, H., Albanyan, H., Yang, M., 

Liang, J. J., Yu, A., Shtukenberg, A., Poloni, L. N., Kho-

lodovych, V., Tischfield, J. A., Goldfarb, D. S., Ward, 

M. D., & Sahota, A. (2016). l-Cystine Diamides as l-

Cystine Crystallization Inhibitors for Cystinuria. Jour-

nal of medicinal chemistry, 59(15), 7293–7298.  
HTTPS://DOI.ORG/10.1021/ACS.JMEDCHEM.6B00647 

[12] Khan, S. R., Pearle, M. S., Robertson, W. G., Gambaro, 

G., Canales, B. K., Doizi, S., Traxer, O., & Tiselius, H. 

G. (2016). Kidney stones. Nature reviews. Disease pri-

mers, 2, 16008.  
HTTPS://DOI.ORG/10.1038/NRDP.2016.8 

[13] Mattoo A, Goldfarb DS. (2008) Cystinuria. Semin 

Nephrol. 28(2):181-91. doi: 10.1016/j.semneph-

rol.2008.01.011. PMID: 18359399.  

[14] Landau, E. H., Shenfeld, O. Z., Pode, D., Shapiro, A., 

Meretyk, S., Katz, G., Katz, R., Duvdevani, M., Hardak, 

B., Cipele, H., Hidas, G., Yutkin, V., & Gofrit, O. N. 

(2009). Extracorporeal shock wave lithotripsy in pre-

pubertal children: 22-year experience at a single in-

stitution with a single lithotriptor. The Journal of urol-

ogy, 182(4 Suppl), 1835–1839.  
HTTPS://DOI.ORG/10.1016/J.JURO.2009.04.084 

[15] Leslie, S. W., Sajjad, H., & Nazzal, L. (2020). Cystinuria. 

In StatPearls. StatPearls Publishing. 

[16] Luther, D. C., Lee, Y. W., Nagaraj, H., Scaletti, F., & 

Rotello, V. M. (2018). Delivery approaches for 

CRISPR/Cas9 therapeutics in vivo: advances and chal-

lenges. Expert opinion on drug delivery, 15(9), 905–

913. HTTPS://DOI.ORG/10.1080/17425247.2018.1517746 

[17] Martell, H. J., Wong, K. A., Martin, J. F., Kassam, Z., 

Thomas, K., & Wass, M. N. (2017). Associating muta-

tions causing cystinuria with disease severity with the 

aim of providing precision medicine. BMC genomics, 

18(Suppl 5), 550.   
HTTPS://DOI.ORG/10.1186/S12864-017-3913-1 

[18] Mendell, J. R., Al-Zaidy, S., Shell, R., Arnold, W. D., 

Rodino-Klapac, L. R., Prior, T. W., Lowes, L., Alfano, L., 

Berry, K., Church, K., Kissel, J. T., Nagendran, S., L'Ital-

ien, J., Sproule, D. M., Wells, C., Cardenas, J. A., Heit-

zer, M. D., Kaspar, A., Corcoran, S., Braun, L., … Kas-

par, B. K. (2017). Single-Dose Gene-Replacement 

Therapy for Spinal Muscular Atrophy. The New Eng-

land journal of medicine, 377(18), 1713–1722.  
HTTPS://DOI.ORG/10.1056/NEJMOA1706198 

https://doi.org/10.1007/s00240-019-01111-7
https://doi.org/10.1002/dvg.23357
https://doi.org/10.1007/s00240-010-0271-8
https://doi.org/10.1016/j.juro.2008.08.057
https://doi.org/10.1097/01.asn.0000029586.17680.e5
https://doi.org/10.1007/s00467-012-2329-z
https://doi.org/10.1371/journal.pone.0137277
https://doi.org/10.1093/hmg/ddg228
https://doi.org/10.1152/ajprenal.00121.2007
https://doi.org/10.1021/acs.jmedchem.6b00647
https://doi.org/10.1038/nrdp.2016.8
https://doi.org/10.1016/j.juro.2009.04.084
https://doi.org/10.1080/17425247.2018.1517746
https://doi.org/10.1186/s12864-017-3913-1
https://doi.org/10.1056/NEJMoa1706198


ARESTY RUTGERS UNDERGRADUATE RESEARCH JOURNAL, VOLUME I, ISSUE IV 

 

[19] McAteer, J. A., & Evan, A. P. (2008). The acute and 

long-term adverse effects of shock wave lithotripsy. 

Seminars in nephrology, 28(2), 200–213.  
HTTPS://DOI.ORG/10.1016/J.SEMNEPHROL.2008.01.003 

[20] Pearle, M. S., Goldfarb, D. S., Assimos, D. G., Curhan, 

G., Denu-Ciocca, C. J., Matlaga, B. R., Monga, M., 

Penniston, K. L., Preminger, G. M., Turk, T. M., White, 

J. R., & American Urological Assocation (2014). Med-

ical management of kidney stones: AUA guide-

line. The Journal of urology, 192(2), 316–324.  
HTTPS://DOI.ORG/10.1016/J.JURO.2014.05.006 

[21] Pereira, D. J. C., Schoolwerth, A. C. & Pais. V. M. 

(2015). Cystinuria: current concepts and future direc-

tions. Clinical Nephrology. 83, 138-146.  doi: 

10.5414/CN108514 

[22] Poloni, L. N., Zhu, Z., Garcia-Vázquez, N., Yu, A. C., 

Connors, D. M., Hu, L., Sahota, A., Ward, M. D., & 

Shtukenberg, A. G. (2017). Role of Molecular Recog-

nition in l-Cystine Crystal Growth Inhibition. Crystal 

growth & design, 17(5), 2767–2781.   
HTTPS://DOI.ORG/10.1021/ACS.CGD.7B00236 

[23] Ringdén, I., & Tiselius, H. G. (2007). Composition and 

clinically determined hardness of urinary tract 

stones. Scandinavian journal of urology and nephrol-

ogy, 41(4), 316–323.  
HTTPS://DOI.ORG/10.1080/00365590601154551 

[24] Rogers, A., Kalakish, S., Desai, R. A., & Assimos, D. G. 

(2007). Management of cystinuria. The Urologic clin-

ics of North America, 34(3), 347–362.  
HTTPS://DOI.ORG/10.1016/J.UCL.2007.04.006 

[25] Sahota, A., Tischfield, J. A., Goldfarb, D. S., Ward, M. 

D., & Hu, L. (2019). Cystinuria: genetic aspects, 

mouse models, and a new approach to therapy. Uro-

lithiasis, 47(1), 57–66.   

HTTPS://DOI.ORG/10.1007/S00240-018-1101-7 

[26] Siener, R., Bitterlich, N., Birwé, H., & Hesse, A. (2021). 

The Impact of Diet on Urinary Risk Factors for Cystine 

Stone Formation. Nutrients, 13(2), 528.  
HTTPS://DOI.ORG/10.3390/NU13020528 

[27] Stenson et al. (2003), The Human Gene Mutation Da-

tabase (HGMD®)  

[28] Sumorok, N., & Goldfarb, D. S. (2013). Update on 

cystinuria. Current opinion in nephrology and hyper-

tension, 22(4), 427–431.  
HTTPS://DOI.ORG/10.1097/MNH.0B013E3283621C5D 

[29] Usawachintachit, M., Sherer, B., Hudnall, M., Tzou, D. 

T., Taguchi, K., Hsi, R. S., Stoller, M., & Chi, T. (2018). 

Clinical Outcomes for Cystinuria Patients with Unilat-

eral Versus Bilateral Cystine Stone Disease. Journal 

of endourology, 32(2), 148–153.  
HTTPS://DOI.ORG/10.1089/END.2017.0335 

[30] Wood, K., Keys, T., Mufarrij, P., & Assimos, D. G. 

(2011). Impact of stone removal on renal function: a 

review. Reviews in urology, 13(2), 73–89.  

[31] Woodard, L. E., Welch, R. C., Veach, R. A., Becker-

mann, T. M., Sha, F., Weinman, E. J., Ikizler, T. A., 

Tischfield, J. A., Sahota, A., & Wilson, M. H. (2019). 

Metabolic consequences of cystinuria. BMC nephrol-

ogy, 20(1), 227.   
HTTPS://DOI.ORG/10.1186/S12882-019-1417-8 

[32] Yang, Y., Albanyan, H., Lee, S., Aloysius, H., Liang, J. 

J., Kholodovych, V., Sahota, A., & Hu, L. (2018). De-

sign, synthesis, and evaluation of l-cystine diamides 

as l-cystine crystallization inhibitors for cystinuria. 

Bioorganic & medicinal chemistry letters, 28(8), 1303–

1308.  
HTTPS://DOI.ORG/10.1016/J.BMCL.2018.03.024

 

 

 

 

 

 

 

 

 

 

 

https://doi.org/10.1016/j.semnephrol.2008.01.003
https://doi.org/10.1016/j.juro.2014.05.006
https://doi.org/10.1021/acs.cgd.7b00236
https://doi.org/10.1080/00365590601154551
https://doi.org/10.1016/j.ucl.2007.04.006
https://doi.org/10.1007/s00240-018-1101-7
https://doi.org/10.3390/nu13020528
https://doi.org/10.1097/MNH.0b013e3283621c5d
https://doi.org/10.1089/end.2017.0335
https://doi.org/10.1186/s12882-019-1417-8
https://doi.org/10.1016/j.bmcl.2018.03.024


ARESTY RUTGERS UNDERGRADUATE RESEARCH JOURNAL, VOLUME I, ISSUE IV 

 

Diana Stachula is a Rutgers Presidential Scholar who graduated summa cum 

laude from the Honors College at Rutgers University - New Brunswick in May 

2022, having completed a B.A. in Genetics and a minor in Psychology. From 

2020-2022, Diana worked as a research assistant for Dr. Amrik Sahota at the 

Human Genetics Institute of New Jersey (HGINJ), where she studied cystinuria 

- a rare genetic disorder that causes the formation of kidney stones. More spe-

cifically, she researched novel pharmacological agents as potential crystal 

growth and stone formation inhibitors. As a lab member, Diana performed gel 

electrophoresis, polymerase chain reactions (PCR), quantitative PCR (qPCR), 

Nanopore sequencing, RNA/DNA extractions from tissue, and various other 

genetic techniques. She has presented her research at several research sym-

posiums, including the university-wide Aresty Undergraduate Research Sym-

posium. Diana also worked as a Peer Instructor at the Aresty Research Center, 

mentoring new research assistants on professional development and com-

municating their research findings. 

 

Currently, Diana is working as an ophthalmic technician and medical assistant in order to gain more experience 

prior to applying to medical school. As a future physician, Diana hopes that she can blend her interests in science 

and medicine by performing clinical research. 


