Diseases of Glycosylation - The Sugar Code - page 369

Table 22.1 Continued

Name Gene defect Activity OMIM

GAG chains

Ehlers - Danlos syndrome
(progeroid form)

XGPT1 Xylose β 1,4 - galactosyltransferase 130070

Hereditary multiple
exostoses - I

EXT1 Proteoglycan β 1,4 - glucuronyl/ α 1,4 - 133700

N - acetylglucosaminyl - transferase

Hereditary multiple
exostoses - II

EXT2 Proteoglycan β 1,4 - glucuronyl/ α 1,4 - 133701

N - acetylglucosaminyl - transferase

Glycosphingolipids and GPI anchor

Amish infantile epilepsy
syndrome

ST3GAL5 α 2,3 - Sialyltransferase (GM3 synth- 609056

ase)

PNH PIGA GPI N - acetylglucosaminyltransferase 311770

Multiple classes of glycosylation

CDG - IIc SLC35C1 Import of GDP - Fuc into Golgi and

export of GMP

266265

CDG - IId B4GALT1 607091

β 1,4 - Galactosyltransferase

CDG - IIf SLC35A1 Import of CMP - Sia into Golgi 603585

Hereditary inclusion body
myopathy

GNE UDP - N - acetylglucosamine

2 - epimerase

600737

Traffi cking disorders

CDG - IIe COG7 Vesicular traffi cking 608779

CDG - IIg COG1 Vesicular traffi cking 611209

CDG - IIh COG8 Vesicular traffi cking 611182

Autosomal recessive cutis laxa ATPV0A2 H + /ATPase, pH regulation in Golgi 611716

mutation identifi ed in the PMM2 gene, which introduces the substitution of an
arginine residue by histidine at position 141 of the protein sequence (R141H), is
very frequent and its estimated incidence is 1 : 80 in most human populations.
However, this mutation is never found in the homozygous state, because this
would completely eliminate phosphomannomutase activity, which is essential to
life. The frequency of the R141H mutation suggests a positive selection pressure
conferring a biological advantage to the carriers of the mutation.
As a result of the sequential and linear assembly of LLO (Figure 22.2 ), defects
in this pathway can be identifi ed by detecting the accumulation of intermediate
LLO structures (Figure 22.3). Most glycosyltransferases involved in LLO synthesis
are hydrophobic proteins embedded in the ER membrane. These glycosyltransfer-
ase activities are diffi cult to measure quantitatively in vitro, meaning that it is also
diffi cult to determine the pathogenic impact of mutations identifi ed in CDG-I. To
address this essential point, researchers take advantage of the strong conservation
of ER N -glycosylation pathways among eukaryotes. It is possible to analyze the