Department Human Molecular Genetics(Hans-Hilger Ropers)

A plethora of novel genes for autosomal recessive forms of ID (ARID)

(Andreas Kuss, Andreas Tzschach, Hao Hu, Masoud Garshasbi, Luciana Musante, Thomas Wienker)

Following up on a previous, pioneering study to identify novel ARID loci and to assess the genetic heterogeneity of this condition3, we have performed array-based SNP typing and linkage mapping in 300 consanguineous Iranian and German families. In 27 of these families, a single homozygous interval was observed, and at least 14 novel ARID loci could be identified7. Starting in 2006, when only three ARID genes had been reported,3 mutation screening of all genes located single linkage intervals has revealed numerous novel genes for syndromic or non- syndromic forms of ID (see Table 1).

Gene

Location

Function

Ethnicity

Reference

GRIK2

6q16.3

Involved in the transmission of light signals from the retina to the hypothalamus, Involved in the maturation of microcircuits and network formation in brain areas

Iranian

Motazacker MM et al., Am J Hum Genet 2007;

81: 792–798

TUSC3

8p22

Putative Mg2+ transporter, required for cellular Mg2+ uptake. Indispensable for normal vertebrate embryonic development.

Iranian, French

Garshasbi M et al., Am

J Hum Genet 2008; 82:

1158–1164

VLDLR

9p24

Part of the reelin signaling pathway, which is involved in neuroblast migration in the cerebral cortex and cerebellum

Iranian, Canadian, Turkish

Abbasi Moheb L et al., Euro J Hum Genet 2008;

16: 270–273

TRAPPC9

8q24.3

Enhancer of the cytokine-induced NF- (kappa)B signaling pathway, having an essential function in post mitotic neurons as opposed to neural progenitors

Iranian, Pakistani, Tunisian, Israeli

Mir A et al., Am J Hum

Genet 2009; 85: 909-915

SRD5A3

4q12

Polyprenol reductase with a crucial role in N-linked protein glycosylation that

is required for converting polyprenol to dolichol.

Iranian, Emirati, Turkish, Polish

Kahrizi K et al., Euro

J Hum Genet 2011;

19:115–117

ZC3H14

14q31.3

May contribute to control of gene expression in human cells through binding poly(A) RNA

Iranian

Pak CH et al., PNAS

2011; 108:12390-95

ST3GAL3

1p34.1

Transfers sialic acid to terminal positions on the carbohydrate groups of glycoproteins and glycolipids that are

key determinants for a variety of cellular recognition processes

Iranian

Hu H et al, Am J Hum

Genet 2011; 89:407-414

NSUN2

5p15.31

RNA methyltransferase that methylates tRNAs, and possibly RNA polymerase III transcripts. May act downstream of Myc to regulate epidermal cell growth and proliferation

Iranian

Abbasi Moheb L et al., Am J Hum Genet 2012;

90: 847-55

ZNF526

19q13.2

Involved in transcriptional regulation, role in regulation of translation

Iranian

Abbasi Moheb L et al., ESHG meeting 2011

Table 1: Novel molecular defects underlying syndromic and non-syndromic ARID.

In 2010, by combining targeted exon enrichment and next generation sequencing, we extended these studies to 136 consanguineous ARID families with more than one linkage interval. In 78 of these, a single plausible causative mutation could be identified, involving 22 known and 50 novel candidate genes. This study, published in 2011,5 quadruplicated the number of (candidate) genes for non- syndromic forms of ARID, which were found to be more common than syndromic forms. For the vast majority of these genes, pathogenic mutations were only seen in a single family. This corroborates our previous observations and suggests that none of these gene defects can account for more than a few percent of all forms of ID in Iran – but it does not exclude founder mutations for ARID in one or several of the 7 or 8 Iranian sub-populations.