Human Chromosome 10 (Aug 2003)

Size: 133 Mb, p/q arm: 35/92 MbFinishedsequence: ~ 124 MB Percentage: 86 %

Assembly completion status

> 5 Mb> 1 Mb

> 0.5 Mb

> 0.1 Mb

> 0.01 Mb

> 50% in golden path

Molecular function of 292 HC10 RefSeq proteins

Euchromatin: ~129 Mb Hetetochromatic region: 3.3-4 Mb

Gene density: ~ 8 genes/MbGenes: 1060G+C content: 42% CpG density: 8.2 islands/MbRepeats: ~43%

Microsatellite density: 4 microsatellites/MbSNP density: 460 SNPs/Mb

Disease genes: 53; clinical phenotypes: 75 Multifactorial disease susceptibility loci: 10 Fragile sites: 7 (2 rare)

heterochromatin

draft seq.

> 1 Mb0.25-1 Mb< 0.25 Mb

Sequencing progress

0%

5%

10%

15%

20%

25%

Cellular

proc

esse

s

Metabo

lism

DNA/RNA mod

ificatio

n

Trans

cription

/Tran

slation Sig

naling

Cell-cel

l commun

ication

Protein

mod

ificatio

nTra

nspo

rt

Cytos

keleta

l

Defens

e/Immun

ity

Cell cy

cle

HC10All HCs

www.ensembl.org/Homo_sapiens/

http://www.sanger.ac.uk/HGP/Chr10/

Physical and genic map of the EPT/ADLTE

critical region (3,5 Mb)

ter

hDHDPS-like

bA56

2L21

bA31

3N18

bA30

E16

bA43

7J2

bA51

2J3

bA39

7J18

bA42

9H9

bA16

2K11

bA39

1J2

bA76

P2

bA14

6P21

bA11

9K6

bA36

1K9

bA40

0G3

bA20

8C17

bA31

0E22

bA16

0P20

bA47

6E15

bA16

4I17

bA7D

5bA

429G

19bA

690P

14bA

44D

15bA

533B

2bA

35J2

3bA

304C

14bA

34E

5bA

196N

24bA

153G

4bA

175O

19bA

208M

2bA

375N

9bA

452K

12bA

445I

23bA

548K

23bA

459F

3

RBP4PDE6C

LGI1CYP2C18

CYP2C9

CYP2C8

CLIM1

PYCS

CD39 DNTT

SLIT1

FRAT1

cenFER1L3

FLJ10540

FRA10AC1

PLCE

AD24

KIAA0608

SMARCA6

CYP2C19 SORBS1

BLNKHTMP10

TLL2

emp70

FRAT2

KIAA0690PGAM1

hCSL4

3077hMMS19FLJ11807

ANKRD2

44050

LOC159371

AL050022

KIAA1795

FLJ13022

SPG9 (~7Mb)

EPT (~3,2Mb)

SHFM3(~1,5Mb)

FRA10A

NEURL

NT

_008

769

(6.7

Mb

)N

T_0

3005

9 (2

0 M

b) 10

q23

.3-q

24

Mutations in LGI1 cause AD lateral temporal lobe epilepsy (EPT)

1 2 3 4 5 7 8

ATG STOP

1639insA

1050-1051delCA1148AgC

6

611delC

IVS3(-3)CgA

598TgC

758delC 1420CgT

136TgC

Normal 557aa

IVS3(-3)CgA 120aa136TgC C46R*

C200R**598TgC238aa (203+35 missense)611delC

758delC 283aa (252+31 missense)**1050-1 delCA 379aa (349+30 missense)

1148AgC E383A1420CgT 473aa**1639insA

553aa (546+7 missense)

EPTP repeatsLRR

LRR-NT LRR-CT

•auditory symptoms, short-lasting sensory aphasia

** auditory symptoms, visual hallucinations

European Consortium for EPT

R. Ottman et. al.

O. Steinlein et al.

Expression of mLgi1 in adult mouse brain

hippocampusCortical layers

Coronal image of half brain

Expression of mLgi1 in synaptic terminals

Adult mouse brain Embryonic neurons (cell bodies and neurites)

Expression of hLGI1 in human temporal and frontal cortex

Temporal cortex Frontal cortex

2002

The superfamily of EPTP genes

LGI family (1-4) TNEP1

VLGR1500aa

Gene Chromosome location Description

LGI1 10q24 Temporal lobe partial epilepsy

LGI2 4p15.2 Expressed in brain

LGI3 8p21 Expressed in brain/ Torsion dystonia (DYT6)

LGI4 19q13.12 Benign familial infantile convulsions (hereditary epilepsy

VLGR1 5q14 Familial febrile convulsions type 4

TNEP1 21q22.3 Myoclonus epilepsy EPM1/Down syndrome critical region/MR

EPTP repeat: a protein interaction domain that links several genes implicated in neurological diseases

Very large G-protein-coupled receptor

ThrombospondinN-terminal domain-EPTP

EMITTING CELL

RECEIVING CELL nucleus

Not

ch

Del

taNe

uraliz

ed

TACEpresenilin

Del

ta

?

Del

taN

otch

Neu

raliz

ed

Ub

Not

ch

?Endocytic vesicle

Dm neuralized (Neur) protein-is an intracellular peripheral membrane protein-stimulates Delta endocytosis and Notch signaling-RING domain is required for Delta accumulation in endosomes but dispensable for Delta signaling;-acts as an E3 ubiquitin ligase

Nec Nec

Dl Dl

Delta over-expressed

Delta + Neur over-expressed

neur

Dm neuralized (neur):- a neurogenic gene implicated in Dm process of sense organ formation

- neur mutations cause hyperplasia of the central & peripheal nervous system, mimicing the excessive neurogenesis phenotype of Notchmutations

mergemerge

The role of drosophila neuralized in Notch signaling

Human NEURL

Drosophila neur

94%

id

enti

ty

Neuralized proteins

RING Zn finger

Mouse Neurl1 574

100 200

NEUZ 1

60 183

300 400 500

291 414 521 560

NEUZ 2

574100 200

60 183

300 400 500

291 414 521 560

1

522 616 73 94

7541143 242

264 292 55 69

104 225

377 680475

366 489 701 741

3 7

15 18

629 637 38 39

314 318367 36930

% i

den

tity

(sim

ilari

ty 5

7%)

(574aa)

(574aa)

(754aa)

neur/EGFPNeurl/EGFP neur/EGFPNeurl/EGFP

Subcellular localization in mammalian cell linesSubcellular localization in Drosophila

neur

Mouse Neuralized (Neurl) is expressedin early embryonic developmental stages