Genome Editing and Human Pluripotent Stem Cell Technologies for in vitro Monogenic Diabetes Modeling

Figures & data

Table 1 Molecular Pathogenesis of Different Types of MODY

MODY Subtype	Gene	Chromosomal Locus	Types of Mutations	Category of Disorder	Pathophysiology	Treatment	Reference
MODY1	HNF4A	20q13.12	Missense, frameshift, splice site, nonsense, indel, deletion, insertion	Transcriptional regulation disorder	Beta cell dysfunction	SU	[99–102]
MODY 2	GCK	7p13	Missense, frameshift, splice site, nonsense, indel, deletion, insertion	Enzyme disorder	Glucose sensing defect	No medication required	[103,104]
MODY 3	HNF1A	12q24.31	Missense, frameshift, splice site, nonsense, indel, deletion, insertion	Transcriptional regulation disorder	Beta cell dysfunction	SU	[57,97,105]
MODY 4	PDX1/IPF1	13q12.2	Missense, nonsense, deletion, insertion	Transcriptional regulation disorder	Beta cell dysfunction	Diet or OAD or Insulin	[94]
MODY 5	HNF1B	17q12	Missense, frameshift, splice site, nonsense, indel, deletion, insertion	Transcriptional regulation disorder	Beta cell dysfunction	Insulin	[106,107]
MODY 6	NEUROD1	2q32	Missense, frameshift, nonsense, indel, deletion, insertion	Transcriptional regulation disorder	Beta cell dysfunction	OAD or Insulin	[108]
MODY 7	KLF11	2p25	Missense	Transcriptional regulation disorder	Beta cell dysfunction	OAD or Insulin	[18,109]
MODY 8	CEL	9q34	Missense, frameshift, indel, deletion, insertion	Protein misfolding disorder	Pancreatic exocrine and endocrine dysfunction	OAD or Insulin	[110]
MODY 9	PAX4	7q32	Missense, splice site, deletion	Transcriptional regulation disorder	Beta cell dysfunction	Diet or OAD or Insulin	[111,112]
MODY10	INS	11p15.5	Missense, splice site, nonsense, indel, insertion	Protein misfolding disorder	Insulin biosynthesis defect	OAD or Insulin	[59]
MODY11	BLK	8p23	Missense	Transcriptional regulation disorder	Insulin secretion defect	Diet or OAD or Insulin	[113]
MODY12	ABCC8	11p15	Missense	Ion channel disorder	Insulin secretion defect	Insulin SU	[114,115]
MODY13	KCNJ11	11p15	Missense	Ion channel disorder	Insulin secretion defect	Insulin SU	[87,94,116]
MODY14	APPL1	3p14.3	Missense, nonsense	Signal transduction disorder	Insulin secretion defect	Diet or OAD or Insulin	[117]

Abbreviations: ABCC8, ATP-binding cassette transporter subfamily C member 8; Akt2, Akt serine/threonine kinase 2; APPL1, Adaptor protein, phosphotyrosine interaction, PH domain, and leucine zipper-containing protein 1; BLK, B-lymphocyte specific tyrosine kinase; CEL, Carboxyl-ester lipase; GCK, Glucokinase; HNFs, Hepatocyte nuclear factors; HNF1A, Hepatocyte nuclear factor 1 alpha; HNF4A, Hepatocyte Nuclear Factor 4 alpha; HNF1B, Hepatocyte Nuclear Factor 1 beta; INS, Insulin; IPF1, Insulin promoter factor 1; IRS, Insulin receptor substrate; KCNJ11, Potassium channel inwardly rectifying subfamily J member 11; KLF11, Krueppel-like factor 11; NEUROD1, Neurogenic differentiation 1; MODY, Maturity-onset diabetes of the young; PAX4, Paired box gene 4; PDX1, Pancreas/duodenum homebox1.

Table 2 Monogenic Causes of Neonatal Diabetes Mellitus

Gene	Chromosomal Locus	Transient Vs Permanent	Clinical Features	Inheritance Pattern	Treatment	References
KCNJ11	11p15.1	Either	Low birth weight, developmental delay, seizures (DEND syndrome), may have other neurologic Features	Spontaneous (80%), AD (20%)	Insulin SU	[116]
ABCC8	11p15.1	Either	Low birth weight	Spontaneous, AD	Insulin SU	[6]
PLAGL1	6q24.2	Transient	Low birth weight, possible IUGR, diagnosed earlier than channel mutations (closer to birth), relapsed cases may respond to SU	Spontaneous, AD for paternal duplications	Insulin	[34]
INS	11p15.5	Either	Low birth weight	Spontaneous (80%), AD (20%) AR (rare: T or P)	Insulin	[118]
GATA6	18q11	Permanent	Pancreatic hypoplasia or agenesis, exocrine insufficiency, cardiac defect	Spontaneous, AD	Insulin	[119,120]
EIF2AK3	2p12	Permanent	Wolcott-Rallison syndrome, skeletal dysplasia (1–2 y old) Episodic acute liver failure, exocrine Pancreatic insufficiency	Spontaneous, AR	Insulin	[121,122]
GCK	7p13	Permanent	Low birth weight	Spontaneous, AR (neonatal diabetes), AD (GCK-MODY)	Insulin	[123]
PTF1A	10p12	Permanent	Neurologic abnormalities, exocrine insufficiency, kidney involvement		Insulin	[124,125]
FOXP3	Xp11.23	Permanent	Autoimmune thyroid disease, exfoliative dermatitis, enteropathy (IPEX syndrome)	X-linked	Insulin	[126]
ZFP57	6p22.1	Transient	Variable phenotype Low birth weight, macroglossia, developmental delay	Spontaneous, maternal Hypomethylation Imprinting	Insulin	[30]
GLIS3	9p24.2	Permanent	Hypothyroidism, kidney cysts, glaucoma, hepatic fibrosis	Spontaneous, AR	Insulin	[127]
PDX1	13q12.1	Permanent	Pancreatic hypoplasia or agenesis, exocrine Insufficiency	Spontaneous, AR (neonatal diabetes), AD (PDX1-MODY)	Insulin	[128]
SLC2A2	3q26.2	Either	Fanconi-Bickel syndrome (hepatomegaly, RTA)	Spontaneous, AR	Insulin	[129]
SLC19A2	1q24.2	Permanent	Neurologic deficit (stroke, seizure) Visual disturbance; cardiac abnormality	Spontaneous, AR	Insulin Thiamine (rarely)	[130]
GATA4	8p23	Permanent	Pancreatic hypoplasia or agenesis, exocrine insufficiency, cardiac defect	Spontaneous, AR	Insulin	[131,132]
NEUROD1	2q31.3	Permanent	Neurologic abnormalities (later), learning difficulties, sensor neural deafness	Spontaneous, AR	Insulin	[133,134]
NEUROG3	10q22.1	Permanent	Diarrhea (due to lack of entero-endocrine cells)	Spontaneous, AR	Insulin	[131,135]
NKX2-2	20p11.22	Permanent	Neurologic abnormalities (later), very low birth weight	Spontaneous, AR	Insulin	[136]
RFX6	6q22.2	Permanent	Low birth weight, intestinal atresia, gall bladder hypoplasia, diarrhea	Spontaneous, AR	Insulin	[137]
IER3IP1	18q21.1	Permanent	Microcephaly, infantile epileptic encephalopathy	Spontaneous, AR	Insulin	[138]
MNX1	7q36	Permanent	Neurologic abnormalities (later)	Spontaneous, AR	Insulin	[139]
HNF1B	17q21	Transient	Pancreatic atrophy, abnormal kidney, and Genitalia development	Spontaneous, AD	Insulin	[140]

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; DEND, developmental delay, epilepsy, and neonatal diabetes; DM, diabetes mellitus; IUGR, intrauterine growth restriction; MODY, maturity onset diabetes of the young; RTA, renal tubular acidosis; SGA, small for gestational age.

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