Table 2.

Loss of function mutations in EXTL3 gene

Mutations	Phenotypes/Clinical Features	Reference
Systemic Extl3-deficient mouse	Embryonic lethality (9 dpc). No detectable HS by high performance liquid chromatography (HPLC) analysis.	[24]
Pancreatic β-cell-specific Extl3- deficient mice	Impaired postnatal islet maturation. Reduced HS level by immunostaining using an anti-HS antibody (3G10).	[24]
Podocyte-specific Extl3-deficient mice	Irregularities in the glomerular basement membrane and effacement of the foot processes. No increase in urinary albumin excretion. Reduced HS level by immunostaining using an anti-HS antibody, HS4C3, which recognizes the 3-O-sulfated domains of HS. HS4C3 (1:10), which especially binds to	[28]
Mutations in human EXTL3 c.1382C > T (p.Pro461Leu)	Lumbar gibbus, kyphoscoliosis, cervical malformations, hypoplastic odontoid peg with cervical instability, epiphyseal abnormalities, and intellectual disability. HS concentration decreased in the urine and serum, while was normal level in fibroblasts.	[29]
c.1537C > T (p.Arg513Cys)	Short stature, metaphyseal abnormalities of the long bones, early death, a lack of T cells, and liver cysts. HS concentration decreased in fibroblasts, while was normal level in the urine and serum.	[29]
c.1970A > G (p.Asn657Ser)	Cervical malformations, hypoplastic odontoid peg with cervical instability, metaphyseal abnormalities of the long bones, early death, idiopathic CD4+ lymphopenia, absolute lack of naive T cells, a typical skin rash, and liver cysts. HS concentration decreased in fibroblasts.	[29]
c.2008 T > G (p.Tyr670Asp)	Short stature, epiphyseal abnormalities, intellectual disability, a lack of T cells, and a typical skin rash. HS concentration decreased in fibroblasts as well as the urine and serum.	[29]
c.1015C > T (p.Arg339Trp)	Generalized platyspondyly with an increased intervertebral space, narrow sarco-ischiatic notches with a trident-shaped acetabula, and short and plump lim bones, metacarpals, and phalanges. Premature craniosynostosis. Narrowing of the cervical canal and severe narrowing of the laryngotracheal tract. Opisthotonus, hyperreflexia, and generalized seizures. Developmental delay, clonic arm movements, and nystagmus. Severe T-cell immunodeficiency. Loger HS chains with an aberrant sulfation pattern. This mutation does not affect the expression level of EXTL3 proteins in fibroblasts.	[30]
c.1382C > T (p.Pro461Leu)	Generalized platyspondyly with an increased intervertebral space, narrow sarco-ischiatic notches with a trident-shaped acetabula, and short and thick limb bones, metacarpals, and phalanges. Narrowing of the cervical canal. Muscular hypotonia and marked developmental delay. Severe T-cell immunodeficiency. This mutation does not affect the expression level of EXTL3 proteins in peripheral blood mononuclear cells.	[30]
c.953C > T (p.Pro318Leu)	Severe platyspondyly, kyphoscoliosis, pelvic distortion, constriction of the proximal femora, and brachydactyly. Glycosyltransferase activity of EXTL3 significantly decreased. This mutation does not affect protein stability of EXTL3.	[31]